View source for Alzheimer's disease

{{Short description|Progressive neurodegenerative disease}}
{{Redirect|Alzheimer|the [[eponym]]|Alois Alzheimer|other uses|Alzheimer (disambiguation)}}
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{{Use British English|date=March 2022}}
{{Use dmy dates|date=July 2023}}
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{{Infobox medical condition (new)
| name = Alzheimer's disease
| image = Brain-ALZH.png
| caption = Diagram of a normal [[human brain|brain]] compared to the brain of a person with Alzheimer's
| pronounce = {{IPAc-en|ˈ|æ|l|t|s|h|aɪ|m|ər|z}}, {{IPAc-en|usalso|ˈ|ɑː|l|t|s|-}}
| field = [[Neurology]]
| synonyms = Alzheimer's dementia
| symptoms = [[Memory loss]], [[primary progressive aphasia|problems with language]], [[Orientation (mental)|disorientation]], [[mood swing]]s<ref name=Knopman2021 /><ref name=WHO2023/>
| complications = [[Infection]]s, [[Falls in older adults|falls]] and [[aspiration pneumonia]] in the terminal stage<ref name=":0">{{Cite web |title=Ask the Doctors - What is the cause of death in Alzheimer's disease? |url=https://www.uclahealth.org/news/ask-the-doctors-what-is-the-cause-of-death-in-alzheimers-disease |access-date=2024-03-18 |website=www.uclahealth.org |language=en}}</ref>
| onset = Over 65 years old<ref name=Mend2012 />
| duration = Long term<ref name=WHO2023/>
| causes = Poorly understood<ref name=Knopman2021 />
| risks = [[Genetics]], [[head injury|head injuries]], [[major depressive disorder|clinical depression]], [[hypertension]],<ref name=Knopman2021 /> [[psychological stress]],<ref name="Yu 1201–1209"/> lack of physical<ref name=Cheng2016/> and mental<ref name="Yu 1201–1209"/><ref name=Vina2018/> exercise
| diagnosis = Based on symptoms and [[cognitive test]]ing after ruling out other possible causes<ref name=NICE2014Diag />
| differential = [[Normal brain aging]],<ref name=Knopman2021 /> [[Lewy body dementia]],<ref name=Gomperts2016>{{cite journal | vauthors = Gomperts SN | title = Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia | journal = Continuum | volume = 22 | issue = 2 Dementia | pages = 435–463 | date = April 2016 | pmid = 27042903 | pmc = 5390937 | doi = 10.1212/CON.0000000000000309 | type = Review  |issn = 1080-2371}}</ref> [[Trisomy 21]]<ref name=Lott2019>{{cite journal |vauthors=Lott IT, Head E |title=Dementia in Down syndrome: unique insights for Alzheimer disease research |journal=Nat Rev Neurol |volume=15 |issue=3 |pages=135–147 |date=March 2019 |pmid=30733618 |pmc=8061428 |doi=10.1038/s41582-018-0132-6 }}</ref>
| prevention = 
| treatment = 
| medication = [[Acetylcholinesterase inhibitor]]s, [[NMDA receptor antagonist]]s<ref name="mayo">{{Cite web |date=2023-08-30 |title=How Alzheimer's drugs help manage symptoms |url=https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers/art-20048103 |access-date=2024-03-19 |website=Mayo Clinic |language=en}}</ref>
| prognosis = Life expectancy 3–12 years<ref name="mayo" /><ref name="schaffert">{{cite journal | vauthors = Schaffert J, LoBue C, Hynan LS, Hart J, Rossetti H, Carlew AR, Lacritz L, White CL, Cullum CM | title = Predictors of Life Expectancy in Autopsy-Confirmed Alzheimer's Disease | journal = Journal of Alzheimer's Disease | volume = 86 | issue = 1 | pages = 271–281 | date = 2022 | pmid = 35034898 | pmc = 8966055 | doi = 10.3233/JAD-215200 }}</ref><ref name="todd">{{cite journal | vauthors = Todd S, Barr S, Roberts M, Passmore AP | title = Survival in dementia and predictors of mortality: a review | journal = International Journal of Geriatric Psychiatry | volume = 28 | issue = 11 | pages = 1109–1124 | date = November 2013 | pmid = 23526458 | doi = 10.1002/gps.3946 }}</ref>
| frequency = 50 million (2020)<ref name=Breijyeh2020 />
| deaths = 
| named after = [[Alois Alzheimer]]
}}

<!-- Definition and symptoms -->
'''Alzheimer's disease''' ('''AD''') is a [[neurodegenerative disease]] that usually starts slowly and progressively worsens.<ref name=WHO2023>{{cite web|date=15 March 2023|title=Dementia Fact sheet|url=https://www.who.int/en/news-room/fact-sheets/detail/dementia|publisher=World Health Organization|access-date=10 July 2023 }}</ref> It is the cause of 60–70% of cases of [[dementia]].<ref name=WHO2023/><ref name=Simon2018p111 /> The most common early symptom is difficulty in [[short-term memory|remembering recent events]].<ref name=Knopman2021 /> As the disease advances, symptoms can include [[aphasia|problems with language]], [[Orientation (mental)|disorientation]] (including easily getting lost), [[mood swing]]s, loss of [[motivation]], [[self-neglect]], and [[challenging behaviour|behavioral issues]].<ref name=WHO2023/> As a person's condition declines, they often [[Solitude|withdraw from family and society]].<ref name=BMJ2009>{{cite journal | vauthors = Burns A, Iliffe S | title = Alzheimer's disease | journal = BMJ | volume = 338 | pages = b158 | date = February 2009 | pmid = 19196745 | doi = 10.1136/bmj.b158 | s2cid = 8570146 }}</ref> Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to twelve years.<ref name="mayo" /><ref name="schaffert" /><ref name="todd" />

<!-- Cause, diagnosis and prevention -->
The causes of Alzheimer's disease remain poorly understood.<ref name=BMJ2009 /> There are many environmental and genetic [[risk factor]]s associated with its development. The strongest genetic risk factor is from an [[allele]] of [[apolipoprotein E]].<ref name=Long /><ref name=NIA2021>{{cite web |title=Study reveals how APOE4 gene may increase risk for dementia |url=https://www.nia.nih.gov/news/study-reveals-how-apoe4-gene-may-increase-risk-dementia |publisher=National Institute on Aging |date=16 March 2021 |access-date=17 March 2021 |archive-date=17 March 2021 |archive-url=https://web.archive.org/web/20210317180050/https://www.nia.nih.gov/news/study-reveals-how-apoe4-gene-may-increase-risk-dementia |url-status=live }}</ref> Other risk factors include a history of [[head injury]], [[clinical depression]], and [[high blood pressure]].<ref name=Knopman2021 /> The progression of the disease is largely characterized by the accumulation of [[Proteinopathy|malformed protein deposits]] in the [[cerebral cortex]], called [[amyloid plaques]] and [[neurofibrillary tangles]]. These misfolded [[Protein_aggregation|protein aggregates]] interfere with normal cell function, and over time lead to irreversible [[Neurodegenerative disease|degeneration of neurons]] and loss of [[Synapse|synaptic connections]] in the [[human brain|brain]].<ref name="NIA2023">{{cite web |title=Alzheimer's Disease Fact Sheet |url=https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet |url-status=dead |archive-url=https://web.archive.org/web/20220323200727/https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet |archive-date=23 March 2022 |access-date=23 March 2022 |publisher=National Institute on Aging}}</ref> A probable diagnosis is based on the history of the illness and [[cognitive test]]ing, with [[medical imaging]] and [[blood test]]s to rule out other possible causes.<ref name=NICE2014Diag>{{cite web |title=Dementia diagnosis and assessment |publisher=National Institute for Health and Care Excellence (NICE) |url=http://pathways.nice.org.uk/pathways/dementia/dementia-diagnosis-and-assessment.pdf|access-date=30 November 2014|url-status=dead |archive-url=https://web.archive.org/web/20141205184403/http://pathways.nice.org.uk/pathways/dementia/dementia-diagnosis-and-assessment.pdf|archive-date=5 December 2014}}</ref><ref>{{cite report | title=Dementia: assessment, management and support for people living with dementia and their carers | publisher=[[National Institute for Health and Care Excellence]] (NICE) | date=20 June 2018 | url=https://www.nice.org.uk/guidance/ng97 | access-date=8 July 2023 | id=NG97 }}</ref> Initial symptoms are often mistaken for [[normal brain aging]].<ref name=BMJ2009 /> [[Histopathology|Examination of brain tissue]] is needed for a definite diagnosis, but this can only take place [[postmortem studies|after death]].<ref name=Khan2020 /><ref name=Gauthreaux2020 />

<!-- Management -->
No treatments can stop or reverse its progression, though some may temporarily improve symptoms.<ref name=WHO2023/> A healthy diet, physical activity, and [[social engagement]] are generally beneficial in aging, and may help in reducing the risk of cognitive decline and Alzheimer's.<ref name="NIA2023" /> Affected people become increasingly reliant on others for assistance, often placing a burden on [[Dementia caregiving|caregivers]].<ref name=Thom2007 /> The pressures can include social, psychological, physical, and economic elements.<ref name=Thom2007>{{cite journal | vauthors = Thompson CA, Spilsbury K, Hall J, Birks Y, Barnes C, Adamson J | title = Systematic review of information and support interventions for caregivers of people with dementia | journal = BMC Geriatrics | volume = 7 | pages = 18 | date = July 2007 | pmid = 17662119 | pmc = 1951962 | doi = 10.1186/1471-2318-7-18 | doi-access = free }}</ref> Exercise programs may be beneficial with respect to [[activities of daily living]] and can potentially improve outcomes.<ref name=Forb2015>{{cite journal | vauthors = Forbes D, Forbes SC, Blake CM, Thiessen EJ, Forbes S | title = Exercise programs for people with dementia | journal = The Cochrane Database of Systematic Reviews | volume = 132 | issue = 4 | pages = CD006489 | date = April 2015 | pmid = 25874613 | doi = 10.1002/14651858.CD006489.pub4 | pmc = 9426996 | type = Submitted manuscript }}</ref> Behavioral problems or [[psychosis]] due to dementia are sometimes treated with [[antipsychotic]]s, but this has an increased risk of early death.<ref>{{cite web  |title=Low-dose antipsychotics in people with dementia |publisher=National Institute for Health and Care Excellence (NICE) |url=https://www.nice.org.uk/advice/ktt7/resources/non-guidance-lowdose-antipsychotics-in-people-with-dementia-pdf|access-date=29 November 2014|url-status=dead |archive-url=https://web.archive.org/web/20141205183329/https://www.nice.org.uk/advice/ktt7/resources/non-guidance-lowdose-antipsychotics-in-people-with-dementia-pdf|archive-date=5 December 2014}}</ref><ref>{{cite web |date=16 June 2008 |title=Information for Healthcare Professionals: Conventional Antipsychotics |publisher=US Food and Drug Administration |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124830.htm|access-date=29 November 2014 |archive-url=https://web.archive.org/web/20141129015823/https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm124830.htm|archive-date=29 November 2014 | url-status=dead }}</ref> 

<!-- Epidemiology, history, society, and research-->
As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease.<ref name=Breijyeh2020 /> It most often begins in people over 65&nbsp;years of age, although up to 10% of cases are [[Early-onset Alzheimer's disease|early-onset]] impacting those in their 30s to mid-60s.<ref name=NIA2019>{{cite web |title=Alzheimer's Disease Fact Sheet |url=https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet |publisher=National Institute on Aging |access-date=25 January 2021 |archive-date=24 January 2021 |archive-url=https://web.archive.org/web/20210124194838/https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet |url-status=live }}</ref><ref name=Mend2012>{{cite journal | vauthors = Mendez MF | title = Early-onset Alzheimer's disease: nonamnestic subtypes and type 2 AD | journal = Archives of Medical Research | volume = 43 | issue = 8 | pages = 677–685 | date = November 2012 | pmid = 23178565 | pmc = 3532551 | doi = 10.1016/j.arcmed.2012.11.009 }}</ref> It affects about 6% of people 65 years and older,<ref name=BMJ2009 /> and women more often than men.<ref>{{cite journal |vauthors=Zhu D, Montagne A, Zhao Z |title=Alzheimer's pathogenic mechanisms and underlying sex difference |journal=Cell Mol Life Sci |volume=78 |issue=11 |pages=4907–4920 |date=June 2021 |pmid=33844047 |pmc=8720296 |doi=10.1007/s00018-021-03830-w }}</ref> The disease is named after German psychiatrist and pathologist [[Alois Alzheimer]], who first described it in 1906.<ref name=pmid9661992 /> Alzheimer's financial burden on society is large, with an estimated global annual cost of {{US$|1}}{{nbsp}}trillion.<ref name=Breijyeh2020 /> It is ranked as the [[List of causes of death by rate|seventh leading cause of death]] worldwide.<ref>{{Cite web |title=The top 10 causes of death |url=https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death |access-date=2024-03-19 |website=www.who.int |language=en}}</ref> 
<!-- Public and private funding of Alzheimer's research -->

Given the widespread impacts of Alzheimer's disease, both basic-science and health funders in many countries support Alzheimer's research at large scales. For example, the US [[National Institutes of Health]] program for Alzheimer's research, the National Plan to Address Alzheimer’s Disease, has a budget of US$3.98 billion for fiscal year 2026.<ref>{{Cite web|vauthors=Bertagnolli MM|title=Fiscal Year 2026 NIH Professional Judgment Budget for Alzheimer's Disease and Related Dementias Research: Advancing Progress in Dementia Research |url=https://www.nia.nih.gov/about/budget/fy26-professional-judgment-budget-proposal|date=5 August 2024|access-date=23 September 2024 |publisher=US National Institutes of Health}}</ref> In the [[European Union]], the 2020 [[Horizon Europe]] research programme awarded over €570 million for dementia-related projects.<ref>{{Cite journal|url=https://www.alzheimer-europe.org/policy/eu-action/horizon-europe-research-programme-0?language_content_entity=en|title=Horizon Europe research programme|via=www.alzheimer-europe.org}}</ref>
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==Signs and symptoms==
The course of Alzheimer's is generally described in three stages, with a progressive pattern of [[cognitive]] and [[functional symptom|functional]] [[Disability|impairment]].<ref name=NHS2018>{{cite web|title=Alzheimer's disease – Symptoms|url=https://www.nhs.uk/conditions/alzheimers-disease/symptoms/|website=[[National Health Service]] (NHS)|date=10 May 2018|access-date=25 January 2021|archive-date=30 January 2021|archive-url=https://web.archive.org/web/20210130034141/https://www.nhs.uk/conditions/alzheimers-disease/symptoms/|url-status=live}}</ref><ref name=NIA2019 /> The three stages are described as early or mild, middle or moderate, and late or severe.<ref name=NHS2018 /> The disease is known to target the [[hippocampus]] which is associated with [[memory]], and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment.<ref name=NIA2023/>

===First symptoms===
[[File:Alzheimer’s Disease, Spreads through the Brain (24524716351).jpg|thumb|Stages of [[atrophy]] in Alzheimer's]]
The first symptoms are often mistakenly attributed to [[aging]] or [[stress (biology)|stress]].<ref name=Waldemar2007>{{cite journal | vauthors = Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B |title = Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline | journal = European Journal of Neurology | volume = 14 | issue = 1 | pages = e1-26 | date = January 2007 | pmid = 17222085 | doi = 10.1111/j.1468-1331.2006.01605.x | s2cid = 2725064 | doi-access = free | title-link = doi | author6-link = Martin Rossor }}</ref> Detailed [[neuropsychological test]]ing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for [[medical diagnosis|diagnosis]] of Alzheimer's disease.<ref name=pmid15324363>{{cite journal | vauthors = Bäckman L, Jones S, Berger AK, Laukka EJ, Small BJ | title = Multiple cognitive deficits during the transition to Alzheimer's disease | journal = Journal of Internal Medicine | volume = 256 | issue = 3 | pages = 195–204 | date = September 2004 | pmid = 15324363 | doi = 10.1111/j.1365-2796.2004.01386.x | s2cid = 37005854 | doi-access = free | title-link = doi }}</ref> These early symptoms can affect the most complex [[activities of daily living]].<ref>{{cite journal | vauthors = Nygård L | title = Instrumental activities of daily living: a stepping-stone towards Alzheimer's disease diagnosis in subjects with mild cognitive impairment? | journal = Acta Neurologica Scandinavica. Supplementum | volume = 179 | issue = s179 | pages = 42–46 | year = 2003 | pmid = 12603250 | doi = 10.1034/j.1600-0404.107.s179.8.x | s2cid = 25313065 }}</ref> The most noticeable deficit is [[short term memory]] loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.<ref name=pmid15324363 />

Subtle problems with the [[executive functions]] of [[attention|attentiveness]], [[planning]], flexibility, and [[abstraction|abstract thinking]], or impairments in [[semantic memory]] (memory of meanings, and concept relationships) can also be symptomatic of the early stages of Alzheimer's disease.<ref name=pmid15324363 /> [[Apathy]] and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease.<ref name=Deardorff>{{cite book | vauthors = Deardorff WJ, Grossberg GT | title = Psychopharmacology of Neurologic Disease | chapter = Behavioral and psychological symptoms in Alzheimer's dementia and vascular dementia | series = Handbook of Clinical Neurology | volume = 165 | pages = 5–32 | date = 2019 | publisher = Elsevier | pmid = 31727229 | doi = 10.1016/B978-0-444-64012-3.00002-2 | isbn = 978-0-444-64012-3 | s2cid = 208037448 }}</ref><ref>{{cite book |title=Bradley's neurology in clinical practice|year=2012 |publisher=Elsevier/Saunders|location=Philadelphia, PA|isbn=978-1-4377-0434-1 |vauthors=Murray ED, Buttner N, Price BH|edition=6th|veditors=Bradley WG, Daroff RB, Fenichel GM, Jankovic J |chapter=Depression and Psychosis in Neurological Practice}}</ref> People with objective signs of cognitive impairment, but not more severe symptoms, may be diagnosed with [[mild cognitive impairment]] (MCI). If memory loss is the predominant symptom of MCI, it is termed [[amnestic MCI]] and is frequently seen as a [[prodromal]] or early stage of Alzheimer's disease.<ref name=Petersen>{{cite journal | vauthors = Petersen RC, Lopez O, Armstrong MJ, Getchius TS, Ganguli M, Gloss D, Gronseth GS, Marson D, Pringsheim T, Day GS, Sager M, Stevens J, Rae-Grant A | title = Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 90 | issue = 3 | pages = 126–135 | date = January 2018 | pmid = 29282327 | pmc = 5772157 | doi = 10.1212/WNL.0000000000004826 }}</ref> Amnestic MCI has a greater than 90% likelihood of being associated with Alzheimer's.<ref name=Atri2019 />

===Early stage===
In people with Alzheimer's disease, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, [[perception]] ([[agnosia]]), or execution of movements ([[apraxia]]) are more prominent than memory problems.<ref name=pmid10653284>{{cite journal | vauthors = Förstl H, Kurz A | title = Clinical features of Alzheimer's disease | journal = European Archives of Psychiatry and Clinical Neuroscience | volume = 249 | issue = 6 | pages = 288–290 | year = 1999 | pmid = 10653284 | doi = 10.1007/s004060050101 | s2cid = 26142779 }}</ref> Alzheimer's disease does not affect all memory capacities equally. [[long-term memory|Older memories]] of the person's life ([[episodic memory]]), facts learned ([[semantic memory]]), and [[implicit memory]] (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories.<ref name=pmid1300219>{{cite journal | vauthors = Carlesimo GA, Oscar-Berman M | title = Memory deficits in Alzheimer's patients: a comprehensive review | journal = Neuropsychology Review | volume = 3 | issue = 2 | pages = 119–169 | date = June 1992 | pmid = 1300219 | doi = 10.1007/BF01108841 | s2cid = 19548915 }}</ref><ref name=pmid8821346>{{cite journal | vauthors = Jelicic M, Bonebakker AE, Bonke B | title = Implicit memory performance of patients with Alzheimer's disease: a brief review | journal = International Psychogeriatrics | volume = 7 | issue = 3 | pages = 385–392 | year = 1995 | pmid = 8821346 | doi = 10.1017/S1041610295002134 | s2cid = 9419442 }}</ref>

[[primary progressive aphasia|Language problems]] are mainly characterised by a shrinking [[vocabulary]] and decreased word [[fluency]], leading to a general impoverishment of oral and [[written language]].<ref name=pmid10653284 /><ref name=pmid1856925>{{cite journal | vauthors = Taler V, Phillips NA | title = Language performance in Alzheimer's disease and mild cognitive impairment: a comparative review | journal = Journal of Clinical and Experimental Neuropsychology | volume = 30 | issue = 5 | pages = 501–556 | date = July 2008 | pmid = 18569251 | doi = 10.1080/13803390701550128 | s2cid = 37153159 }}</ref> In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately.<ref name=pmid10653284 /><ref name=pmid1856925 /><ref name=pmid7967534>{{cite journal | vauthors = Frank EM | title = Effect of Alzheimer's disease on communication function | journal = Journal of the South Carolina Medical Association | volume = 90 | issue = 9 | pages = 417–423 | date = September 1994 | pmid = 7967534 }}</ref> While performing [[fine motor skill|fine motor tasks]] such as writing, drawing, or dressing, certain movement coordination and planning difficulties ([[apraxia]]) may be present; however, they are commonly unnoticed.<ref name=pmid10653284 /> As the disease progresses, people with Alzheimer's disease can often continue to perform many tasks independently; however, they may need assistance or supervision with the most cognitively demanding activities.<ref name=pmid10653284 />

===Middle stage===
Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living.<ref name=pmid10653284 /> Speech difficulties become evident due to an inability to [[Anomic aphasia|recall vocabulary]], which leads to frequent incorrect word substitutions ([[paraphasia]]s). Reading and writing skills are also progressively lost.<ref name=pmid10653284 /><ref name=pmid7967534 /> Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so the risk of falling increases.<ref name=pmid10653284 /> During this phase, memory problems worsen, and the person may fail to recognise close relatives.<ref name=pmid10653284 /> [[Long-term memory]], which was previously intact, becomes impaired.<ref name=pmid10653284 />

Behavioral and [[neuropsychiatric]] changes become more prevalent. Common manifestations are [[Wandering (dementia)|wandering]], [[irritability]] and [[emotional lability]], leading to crying, outbursts of unpremeditated [[aggression]], or resistance to caregiving.<ref name=pmid10653284 /> [[Sundowning]] can also appear.<ref>{{cite journal | vauthors = Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A | title = Sundowning and circadian rhythms in Alzheimer's disease | journal = The American Journal of Psychiatry | volume = 158 | issue = 5 | pages = 704–711 | date = May 2001 | pmid = 11329390 | doi = 10.1176/appi.ajp.158.5.704 | s2cid = 10492607 }}</ref> Approximately 30% of people with Alzheimer's disease develop [[Delusional misidentification syndrome|illusionary misidentifications]] and other [[delusion]]al symptoms.<ref name=pmid10653284 /> Subjects also lose insight of their disease process and limitations ([[anosognosia]]).<ref name=pmid10653284 /> [[Urinary incontinence]] can develop.<ref name=pmid10653284 /> These symptoms create [[stress (biology)|stress]] for relatives and caregivers, which can be reduced by moving the person from [[home care]] to other [[Nursing home|long-term care facilities]].<ref name=pmid10653284 /><ref name=pmid7806732>{{cite journal | vauthors = Gold DP, Reis MF, Markiewicz D, Andres D | title = When home caregiving ends: a longitudinal study of outcomes for caregivers of relatives with dementia | journal = Journal of the American Geriatrics Society | volume = 43 | issue = 1 | pages = 10–16 | date = January 1995 | pmid = 7806732 | doi = 10.1111/j.1532-5415.1995.tb06235.x | s2cid = 29847950 }}</ref>

===Late stage===
[[File:Alzheimers brain.jpg|thumb|A normal brain on the left and a late-stage Alzheimer's brain on the right]]
During the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers.<ref name=NIA2023/><ref name=NHS2018 /><ref name=pmid10653284 /> Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.<ref name=pmid10653284 /><ref name=pmid7967534 /> Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme [[apathy]] and [[Fatigue (medical)|exhaustion]] are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently; [[musculature|muscle mass]] and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of [[pressure ulcer]]s or [[pneumonia]], not the disease itself.<ref name=pmid10653284 /><!-- cites previous 4 sentences --> In some cases, there is a [[paradoxical lucidity]] immediately before death, where there is an unexpected recovery of mental clarity.<ref>{{cite journal |vauthors = Mashour GA, Frank L, Batthyany A, Kolanowski AM, Nahm M, Schulman-Green D, Greyson B, Pakhomov S, Karlawish J, Shah RC |title=Paradoxical lucidity: A potential paradigm shift for the neurobiology and treatment of severe dementias |journal=Alzheimer's & Dementia |volume=15 |issue=8 |pages=1107–1114 |date=August 2019 |pmid=31229433 |doi=10.1016/j.jalz.2019.04.002 |s2cid=195063786 |hdl=2027.42/153062 |hdl-access=free }}</ref>

==Causes==

Alzheimer's disease is believed to occur when abnormal amounts of [[amyloid beta]] (Aβ), accumulating extracellularly as [[amyloid plaques]] and [[tau protein]]s, or intracellularly as [[neurofibrillary tangle]]s, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function.<ref>{{cite web | title=Alzheimer's disease – Causes | website=[[National Health Service]] (NHS) | date=24 April 2023 | url=https://www.nhs.uk/conditions/alzheimers-disease/causes/ | access-date=10 July 2023 | archive-url=https://web.archive.org/web/20200929103158/https://www.nhs.uk/conditions/alzheimers-disease/causes/ |archive-date=29 September 2020 | url-status = live }}</ref><ref name=Tackenberg>{{cite journal | vauthors = Tackenberg C, Kulic L, Nitsch RM | title = Familial Alzheimer's disease mutations at position 22 of the amyloid β-peptide sequence differentially affect synaptic loss, tau phosphorylation and neuronal cell death in an ex vivo system | journal = PLOS ONE | volume = 15 | issue = 9 | pages = e0239584 | date = 2020 | pmid = 32966331 | pmc = 7510992 | doi = 10.1371/journal.pone.0239584 | bibcode = 2020PLoSO..1539584T | doi-access = free | title-link = doi }}</ref> This altered [[autophagy|protein clearance ability]] is age-related, regulated by brain cholesterol,<ref name=WangHao>{{cite journal | vauthors = Wang H, Kulas JA, Wang C, Holtzman DM, Ferris HA, Hansen SB | title = Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 118 | issue = 33 | pages = e2102191118 | date = August 2021 | pmid = 34385305 | pmc = 8379952 | doi = 10.1073/pnas.2102191118|issn=0027-8424 | s2cid = 236998499 | doi-access = free | title-link = doi | bibcode = 2021PNAS..11802191W }}</ref> and associated with other neurodegenerative diseases.<ref name=Vilchez>{{cite journal | vauthors = Vilchez D, Saez I, Dillin A | title = The role of protein clearance mechanisms in organismal ageing and age-related diseases | journal = Nature Communications | volume = 5 | issue = | pages = 5659 | date = December 2014 | pmid = 25482515 | doi = 10.1038/ncomms6659 | bibcode = 2014NatCo...5.5659V | doi-access = free | title-link = doi }}</ref><ref name=OUP>{{cite book| vauthors = Jacobson M, McCarthy N |title=Apoptosis |date=2002|publisher=Oxford University Press|location=Oxford, OX|isbn=0-19-963849-7|page=290}}</ref>

The cause for most Alzheimer's cases is still mostly unknown,<ref name=Breijyeh2020>{{cite journal | vauthors = Breijyeh Z, Karaman R | title = Comprehensive Review on Alzheimer's Disease: Causes and Treatment | journal = Molecules | volume = 25 | issue = 24 | date = December 2020 | page = 5789 | pmid = 33302541 | pmc = 7764106 | doi = 10.3390/molecules25245789 | type = Review | doi-access = free | title-link = doi }}</ref> except for 1–2% of cases where deterministic genetic differences have been identified.<ref name=Long /> Several competing [[hypotheses]] attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis.<ref name=Breijyeh2020 />

The oldest hypothesis, on which most drug therapies are based, is the [[Cholinergic#Cholinergic_hypothesis_of_Alzheimer's_disease|cholinergic hypothesis]], which proposes that Alzheimer's disease is caused by reduced synthesis of the neurotransmitter [[acetylcholine]].<ref name=Breijyeh2020 /> The loss of [[cholinergic neuron]]s noted in the [[limbic system]] and cerebral cortex, is a key feature in the progression of Alzheimer's.<ref name=Petersen /> The 1991 [[Biochemistry of Alzheimer's disease#Amyloid hypothesis|amyloid hypothesis]] postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease.<ref name=pmid1763432>{{cite journal | vauthors = Hardy J, Allsop D | title = Amyloid deposition as the central event in the aetiology of Alzheimer's disease | journal = Trends in Pharmacological Sciences | volume = 12 | issue = 10 | pages = 383–388 | date = October 1991 | pmid = 1763432 | doi = 10.1016/0165-6147(91)90609-V }}</ref><ref name=pmid11801334>{{cite journal | vauthors = Mudher A, Lovestone S | title = Alzheimer's disease-do tauists and baptists finally shake hands? | journal = Trends in Neurosciences | volume = 25 | issue = 1 | pages = 22–26 | date = January 2002 | pmid = 11801334 | doi = 10.1016/S0166-2236(00)02031-2 | s2cid = 37380445 }}</ref> Support for this postulate comes from the location of the gene for the [[amyloid precursor protein]] (APP) on [[chromosome 21]], together with the fact that people with [[trisomy 21]] (Down syndrome) who have an extra [[gene dosage|gene copy]] almost universally exhibit at least the earliest symptoms of Alzheimer's disease by 40&nbsp;years of age.<ref name=Lott2019 /> A specific [[Protein isoform|isoform]] of apolipoprotein, [[APOE4]], is a major genetic risk factor for Alzheimer's disease.<ref name=Simon2018p111 /> While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain.<ref name=pmid7566000>{{cite journal | vauthors = Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K | title = Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein | journal = The New England Journal of Medicine | volume = 333 | issue = 19 | pages = 1242–1247 | date = November 1995 | pmid = 7566000 | doi = 10.1056/NEJM199511093331902 | doi-access = free }}</ref>

===Genetic===

==== Late onset ====
Late-onset Alzheimer's is about 70% [[heritability|heritable]].<ref name=Andrews2023>{{cite journal |vauthors=Andrews SJ, Renton AE, Fulton-Howard B, Podlesny-Drabiniok A, Marcora E, Goate AM |date=April 2023 |title=The complex genetic architecture of Alzheimer's disease: novel insights and future directions |url= |journal=eBioMedicine |volume=90 |pages=104511 |doi=10.1016/j.ebiom.2023.104511 |pmc=10024184 |pmid=36907103}}</ref><ref name=Scheltens2021>{{cite journal |vauthors=Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM |date=April 2021 |title=Alzheimer's disease |url= |journal=Lancet |volume=397 |issue=10284 |pages=1577–1590 |doi=10.1016/S0140-6736(20)32205-4 |pmc=8354300 |pmid=33667416}}</ref> Genetic models in 2020 predict Alzheimer's disease with 90% accuracy.<ref>{{cite journal |vauthors=Sims R, Hill M, Williams J |date=March 2020 |title=The multiplex model of the genetics of Alzheimer's disease |url= https://orca.cardiff.ac.uk/id/eprint/129659/1/Nature%20Neuroscience.pdf|journal=Nat Neurosci |volume=23 |issue=3 |pages=311–322 |doi=10.1038/s41593-020-0599-5 |pmid=32112059|s2cid=256839971 }}</ref> Most cases of Alzheimer's are not [[Familial alzheimer disease|familial]], and so they are termed sporadic Alzheimer's disease.<ref>{{Cite journal |last1=Chávez-Gutiérrez |first1=Lucía |last2=Szaruga |first2=Maria |date=2020-09-01 |title=Mechanisms of neurodegeneration — Insights from familial Alzheimer's disease |url=https://www.sciencedirect.com/science/article/pii/S1084952118302969 |journal=Seminars in Cell & Developmental Biology |series=Gamma Secretase |volume=105 |pages=75–85 |doi=10.1016/j.semcdb.2020.03.005 |pmid=32418657 |issn=1084-9521}}</ref> Of the cases of sporadic Alzheimer's disease, most are classified as late onset where they are developed after the age of 65 years.<ref>{{cite journal |vauthors=Piaceri I, Nacmias B, Sorbi S |title=Genetics of familial and sporadic Alzheimer's disease |journal=Frontiers in Bioscience (Elite Edition) |volume=5 |issue=1 |pages=167–177 |date=January 2013 |pmid=23276979 |doi=10.2741/e605|doi-access=free }}</ref>

The strongest genetic risk factor for sporadic Alzheimer's disease is [[Apolipoprotein E#Alzheimer's disease|APOEε4]].<ref name="NIA2021" /> APOEε4 is one of four alleles of [[apolipoprotein E]] (APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and the [[Apolipoprotein E#Alzheimer's disease|ε4]] allele disrupts this function.<ref name="Perea">{{cite journal |vauthors=Perea JR, Bolós M, Avila J |date=October 2020 |title=Microglia in Alzheimer's Disease in the Context of Tau Pathology |journal=Biomolecules |volume=10 |issue=10 |page=1439 |doi=10.3390/biom10101439 |pmc=7602223 |pmid=33066368 |doi-access=free |title-link=doi}}</ref> Between 40% and 80% of people with Alzheimer's disease possess at least one APOEε4 allele.<ref name="pmid16567625">{{cite journal |vauthors=Mahley RW, Weisgraber KH, Huang Y |date=April 2006 |title=Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=103 |issue=15 |pages=5644–5651 |bibcode=2006PNAS..103.5644M |doi=10.1073/pnas.0600549103 |pmc=1414631 |pmid=16567625 |doi-access=free |title-link=doi}}</ref> The APOEε4 allele increases the risk of the disease by three times in [[Heterozygous|heterozygotes]] and by 15 times in [[Homozygous|homozygotes]].<ref name="pmid16876668">{{cite journal |vauthors=Blennow K, de Leon MJ, Zetterberg H |date=July 2006 |title=Alzheimer's disease |journal=Lancet |volume=368 |issue=9533 |pages=387–403 |doi=10.1016/S0140-6736(06)69113-7 |pmid=16876668 |s2cid=47544338}}</ref> Like many human diseases, environmental effects and genetic modifiers result in incomplete [[penetrance]]. For example, Nigerian [[Yoruba people|Yoruba]] people do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.<ref name="pmid16434658">{{cite journal |vauthors=Hall K, Murrell J, Ogunniyi A, Deeg M, Baiyewu O, Gao S, Gureje O, Dickens J, Evans R, Smith-Gamble V, Unverzagt FW, Shen J, Hendrie H |date=January 2006 |title=Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba |journal=Neurology |volume=66 |issue=2 |pages=223–227 |doi=10.1212/01.wnl.0000194507.39504.17 |pmc=2860622 |pmid=16434658}}</ref><ref name="pmid16278853">{{cite journal |vauthors=Gureje O, Ogunniyi A, Baiyewu O, Price B, Unverzagt FW, Evans RM, Smith-Gamble V, Lane KA, Gao S, Hall KS, Hendrie HC, Murrell JR |date=January 2006 |title=APOE epsilon4 is not associated with Alzheimer's disease in elderly Nigerians |journal=Annals of Neurology |volume=59 |issue=1 |pages=182–185 |doi=10.1002/ana.20694 |pmc=2855121 |pmid=16278853}}</ref>

==== Early onset ====
{{further|Early-onset Alzheimer's disease}}
Only 1–2% of Alzheimer's cases are [[hereditary disease|inherited]] due to [[Dominance (genetics)|autosomal dominant]] effects, as Alzheimer's is highly polygenic. When the disease is caused by autosomal dominant variants, it is known as [[Early-onset Alzheimer's disease#Familial Alzheimer disease|early onset familial Alzheimer's disease]], which is rarer and has a faster rate of progression.<ref name="Long">{{cite journal | vauthors = Long JM, Holtzman DM | title = Alzheimer Disease: An Update on Pathobiology and Treatment Strategies | journal = Cell | volume = 179 | issue = 2 | pages = 312–339 | date = October 2019 | pmid = 31564456 | pmc = 6778042 | doi = 10.1016/j.cell.2019.09.001 }}</ref> Less than 5% of sporadic Alzheimer's disease have an earlier onset,<ref name="Long" /> and early-onset Alzheimer's is about 90% heritable.<ref name=Andrews2023/><ref name=Scheltens2021/> Familial Alzheimer's disease usually implies two or more persons affected in one or more generations.<ref>{{Cite journal |last1=Schramm |first1=C. |last2=Wallon |first2=D. |last3=Nicolas |first3=G. |last4=Charbonnier |first4=C. |date=2022-05-01 |title=What contribution can genetics make to predict the risk of Alzheimer's disease? |url=https://www.sciencedirect.com/science/article/abs/pii/S0035378722005537 |journal=Revue Neurologique |series=International meeting of the French society of neurology : NeuroDegenerative Disease : What will the future bring ? |volume=178 |issue=5 |pages=414–421 |doi=10.1016/j.neurol.2022.03.005 |pmid=35491248 |issn=0035-3787}}</ref><ref>{{Cite journal |last1=Goldman |first1=Jill S. |last2=Van Deerlin |first2=Vivianna M. |date=2018-10-01 |title=Alzheimer's Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing |journal=Molecular Diagnosis & Therapy |language=en |volume=22 |issue=5 |pages=505–513 |doi=10.1007/s40291-018-0347-7 |issn=1179-2000 |pmc=6472481 |pmid=29971646}}</ref><ref>{{cite journal |vauthors=Piaceri I |date=2013 |title=Genetics of familial and sporadic Alzheimer s disease |journal=Frontiers in Bioscience |volume=E5 |issue=1 |pages=167–177 |doi=10.2741/E605 |issn=1945-0494 |pmid=23276979 |doi-access=free}}</ref>

Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encoding [[amyloid-beta precursor protein]] (APP) and [[presenilin]]s [[PSEN1]] and [[PSEN2]].<ref name="Atri2019" /> Most mutations in the APP and presenilin genes increase the production of a small protein called [[amyloid beta]] (Aβ)42, which is the main component of [[amyloid plaques]].<ref name="Selkoe">{{cite journal | vauthors = Selkoe DJ | title = Translating cell biology into therapeutic advances in Alzheimer's disease | journal = Nature | volume = 399 | issue = 6738 Suppl | pages = A23–A31 | date = June 1999 | pmid = 10392577 | doi = 10.1038/19866 | s2cid = 42287088 | doi-access = free | title-link = doi }}</ref> Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain.<ref name="Borchelt">{{cite journal | vauthors = Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, Slunt HH, Wang R, Seeger M, Levey AI, Gandy SE, Copeland NG, Jenkins NA, Price DL, Younkin SG, Sisodia SS | title = Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo | journal = Neuron | volume = 17 | issue = 5 | pages = 1005–1013 | date = November 1996 | pmid = 8938131 | doi = 10.1016/S0896-6273(00)80230-5 | s2cid = 18315650 | doi-access = free | title-link = doi }}</ref> Two other genes associated with autosomal dominant Alzheimer's disease are [[ABCA7]] and [[SORL1]].<ref>{{cite journal | vauthors = Kim JH | title = Genetics of Alzheimer's Disease | journal = Dementia and Neurocognitive Disorders | volume = 17 | issue = 4 | pages = 131–136 | date = December 2018 | pmid = 30906402 | pmc = 6425887 | doi = 10.12779/dnd.2018.17.4.131 }}</ref>

[[Allele]]s in the [[TREM2]] gene have been associated with a three to five times higher risk of developing Alzheimer's disease.<ref>{{cite journal |vauthors=Carmona S, Zahs K, Wu E, Dakin K, Bras J, Guerreiro R |title=The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders |journal=Lancet Neurol |volume=17 |issue=8 |pages=721–730 |date=August 2018 |pmid=30033062 |doi=10.1016/S1474-4422(18)30232-1 |s2cid=51706988 |url=https://discovery.ucl.ac.uk/id/eprint/10056337/ |access-date=21 February 2022 |archive-date=27 March 2022 |archive-url=https://web.archive.org/web/20220327190158/https://discovery.ucl.ac.uk/id/eprint/10056337/ |url-status=live }}</ref>

A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP.<ref name=Tomiyama2010>{{cite journal | vauthors = Tomiyama T | title = [Involvement of beta-amyloid in the etiology of Alzheimer's disease] | journal = Brain and Nerve = Shinkei Kenkyu No Shinpo | volume = 62 | issue = 7 | pages = 691–699 | date = July 2010 | pmid = 20675873 }}</ref> This mutation and its association with Alzheimer's disease was first reported in 2008,<ref name=Tomiyama2008>{{cite journal | vauthors = Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, Takuma H, Kuwano R, Imagawa M, Ataka S, Wada Y, Yoshioka E, Nishizaki T, Watanabe Y, Mori H | title = A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia | journal = Annals of Neurology | volume = 63 | issue = 3 | pages = 377–387 | date = March 2008 | pmid = 18300294 | doi = 10.1002/ana.21321 | s2cid = 42311988 }}</ref> and is known as the Osaka mutation. Only homozygotes with this mutation have an increased risk of developing Alzheimer's disease. This mutation accelerates Aβ oligomerization but the proteins do not form the amyloid fibrils that aggregate into amyloid plaques, suggesting that it is the Aβ oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all the usual pathologies of Alzheimer's disease.<ref name=Tomiyama>{{cite journal | vauthors = Tomiyama T, Shimada H | title = APP Osaka Mutation in Familial Alzheimer's Disease-Its Discovery, Phenotypes, and Mechanism of Recessive Inheritance | journal = International Journal of Molecular Sciences | volume = 21 | issue = 4 | page = 1413 | date = February 2020 | pmid = 32093100 | pmc = 7073033 | doi = 10.3390/ijms21041413 | doi-access = free | title-link = doi }}</ref>

===Hypotheses===

==== Amyloid beta and tau protein ====
[[File:Alzheimers Disease.jpg|300px|thumb|Tau protein abnormalities in neurons may contribute to onset of Alzheimer's disease]]
The [[Biochemistry of Alzheimer's disease#Tau hypothesis|tau hypothesis]] proposes that [[tau protein]] abnormalities initiate the disease cascade.<ref name=tzi/> In this model, [[hyperphosphorylated]] tau begins to pair with other threads of tau as [[paired helical filament]]s. Eventually, they form [[neurofibrillary tangle]]s inside neurons.<ref name="tzi">{{cite journal |vauthors=Tzioras M, Davies C, Newman A, Jackson R, Spires-Jones T |title=Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease |journal=Neuropathology and Applied Neurobiology |volume=45 |issue=4 |pages=327–346 |date=June 2019 |pmid=30394574 |pmc=6563457 |doi=10.1111/nan.12529}}</ref> When this occurs, the [[microtubule]]s disintegrate, destroying the structure of the cell's [[cytoskeleton]] which collapses the neuron's transport system.<ref name=tzi/>

A number of studies connect the misfolded amyloid beta and tau proteins associated with the pathology of Alzheimer's disease, as bringing about [[oxidative stress]] that leads to [[neuroinflammation]].<ref name=Sinyor>{{cite journal | vauthors = Sinyor B, Mineo J, Ochner C | title = Alzheimer's Disease, Inflammation, and the Role of Antioxidants | journal = Journal of Alzheimer's Disease Reports | volume = 4 | issue = 1 | pages = 175–183 | date = June 2020 | pmid = 32715278 | pmc = 7369138 | doi = 10.3233/ADR-200171 }}</ref> This chronic inflammation is also a feature of other neurodegenerative diseases including [[Parkinson's disease]], and [[ALS]].<ref name=Kinney>{{cite journal | vauthors = Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT | title = Inflammation as a central mechanism in Alzheimer's disease | journal = Alzheimer's & Dementia | volume = 4 | issue = | pages = 575–590 | date = 2018 | pmid = 30406177 | pmc = 6214864 | doi = 10.1016/j.trci.2018.06.014 }}</ref> [[Spirochete infection]]s have also been linked to dementia.<ref name=Breijyeh2020 /> [[DNA damage (naturally occurring)|DNA damages]] accumulate in Alzheimer's diseased brains; [[reactive oxygen species]] may be the major source of this DNA damage.<ref>{{cite journal |vauthors=Lin X, Kapoor A, Gu Y, Chow MJ, Peng J, Zhao K, Tang D |title=Contributions of DNA Damage to Alzheimer's Disease |journal=Int J Mol Sci |volume=21 |issue=5 |date=February 2020 |page=1666 |pmid=32121304 |pmc=7084447 |doi=10.3390/ijms21051666 |doi-access=free }}</ref>

==== Sleep ====
[[Sleep disturbance]]s are seen as a possible [[risk factor]] for inflammation in Alzheimer's disease.<ref name="Irwin">{{cite journal | vauthors = Irwin MR, Vitiello MV | title = Implications of sleep disturbance and inflammation for Alzheimer's disease dementia | journal = The Lancet. Neurology | volume = 18 | issue = 3 | pages = 296–306 | date = March 2019 | pmid = 30661858 | doi = 10.1016/S1474-4422(18)30450-2 | s2cid = 58546748 }}</ref> Sleep disruption was previously only seen as a consequence of Alzheimer's disease, but {{As of|2020|lc=y}}, accumulating evidence suggests that this relationship may be [[Correlation does not imply causation#Bidirectional causation: A causes B, and B causes A|bidirectional]].<ref>{{cite journal | vauthors = Lloret MA, Cervera-Ferri A, Nepomuceno M, Monllor P, Esteve D, Lloret A | title = Is Sleep Disruption a Cause or Consequence of Alzheimer's Disease? Reviewing Its Possible Role as a Biomarker | journal = International Journal of Molecular Sciences | volume = 21 | issue = 3 | pages = 1168 | date = February 2020 | pmid = 32050587 | pmc = 7037733 | doi = 10.3390/ijms21031168 | doi-access = free }}</ref>

==== Metal toxicity, smoking, neuroinflammation and air pollution ====
The cellular [[homeostasis]] of [[biometal (biology)|biometals]] such as ionic copper, iron, and zinc is disrupted in Alzheimer's disease, though it remains unclear whether this is produced by or causes the changes in proteins.<ref name=Breijyeh2020 /><ref>{{cite journal |vauthors=Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R |title=Metal Toxicity Links to Alzheimer's Disease and Neuroinflammation |journal=J Mol Biol |volume=431 |issue=9 |pages=1843–1868 |date=April 2019 |pmid=30664867 |pmc=6475603 |doi=10.1016/j.jmb.2019.01.018 }}</ref> Smoking is a significant Alzheimer's disease risk factor.<ref name=Knopman2021>{{cite journal |vauthors = Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, Nixon RA, Jones DT |title=Alzheimer disease |journal=Nature Reviews Disease Primers |volume=7 |issue=1 |pages=33 |date=May 2021 |pmid=33986301 |pmc=8574196 |doi=10.1038/s41572-021-00269-y }}</ref> [[Inflammation#Systemic effects|Systemic markers]] of the [[innate immune system]] are risk factors for late-onset Alzheimer's disease.<ref>{{cite journal | vauthors = Eikelenboom P, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA | title = Neuroinflammation – an early event in both the history and pathogenesis of Alzheimer's disease | journal = Neuro-Degenerative Diseases | volume = 7 | issue = 1–3 | pages = 38–41 | year = 2010 | pmid = 20160456 | doi = 10.1159/000283480 | s2cid = 40048333 }}</ref> [[Neuroplastic effects of pollution|Exposure to air pollution]] may be a contributing factor to the development of Alzheimer's disease.<ref name=Breijyeh2020 />

==== Age-related myelin decline ====
Retrogenesis is a medical [[hypothesis]] that just as the fetus goes through a process of [[neurodevelopment]] beginning with [[neurulation]] and ending with [[myelination]], the brains of people with Alzheimer's disease go through a reverse [[neurodegeneration]] process starting with [[demyelination]] and death of axons (white matter) and ending with the death of grey matter.<ref name="Laks2015">{{cite journal |vauthors=Alves GS, Oertel Knöchel V, Knöchel C, Carvalho AF, Pantel J, Engelhardt E, Laks J |date=2015 |title=Integrating retrogenesis theory to Alzheimer's disease pathology: insight from DTI-TBSS investigation of the white matter microstructural integrity |journal=BioMed Research International |volume=2015 |pages=291658 |doi=10.1155/2015/291658 |pmc=4320890 |pmid=25685779 |doi-access=free |title-link=doi}}</ref> Likewise the hypothesis is, that as infants go through states of [[cognitive development]], people with Alzheimer's disease go through the reverse process of progressive [[cognitive impairment]].<ref name="Kluger1999">{{cite journal |vauthors=Reisberg B, Franssen EH, Hasan SM, Monteiro I, Boksay I, Souren LE, Kenowsky S, Auer SR, Elahi S, Kluger A |date=1999 |title=Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer's and other dementing processes |journal=European Archives of Psychiatry and Clinical Neuroscience |volume=249 |issue=3 |pages=28–36 |doi=10.1007/pl00014170 |pmid=10654097 |s2cid=23410069}}</ref>

According to one theory, dysfunction of [[Oligodendrocyte|oligodendrocytes]] and their associated [[myelin]] during aging contributes to [[axon]] damage, which in turn generates in amyloid production and tau [[hyperphosphorylation]].<ref>{{cite journal | vauthors = Bartzokis G | title = Alzheimer's disease as homeostatic responses to age-related myelin breakdown | journal = Neurobiology of Aging | volume = 32 | issue = 8 | pages = 1341–1371 | date = August 2011 | pmid = 19775776 | pmc = 3128664 | doi = 10.1016/j.neurobiolaging.2009.08.007 }}</ref><ref>{{cite journal | vauthors = Cai Z, Xiao M | title = Oligodendrocytes and Alzheimer's disease | journal = The International Journal of Neuroscience | volume = 126 | issue = 2 | pages = 97–104 | date = 2016 | pmid = 26000818 | doi = 10.3109/00207454.2015.1025778 | s2cid = 21448714 }}</ref> An ''[[in vivo]]'' study employing genetic mouse models to simulate myelin dysfunction and [[amyloidosis]] further reveal that age-related myelin degradation increases sites of Aβ production and distracts [[microglia]] from Aβ plaques, with both mechanisms dually exacerbating amyloidosis.<ref>{{cite journal | vauthors = Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Nazarenko T, Overhoff K, Steixner-Kumar AA, Subramanian S, Arinrad S, Ruhwedel T, Möbius W, Göbbels S, Saher G, Werner HB, Damkou A, Zampar S, Wirths O, Thalmann M, Simons M, Saito T, Saido T, Krueger-Burg D, Kawaguchi R, Willem M, Haass C, Geschwind D, Ehrenreich H, Stassart R, Nave KA | title = Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease | journal = Nature | volume = 618 | issue = 7964 | pages = 349–357 | date = June 2023 | pmid = 37258678 | pmc = 10247380 | doi = 10.1038/s41586-023-06120-6 | bibcode = 2023Natur.618..349D }}</ref> Additionally, [[Comorbidity|comorbidities]] between the demyelinating disease, [[multiple sclerosis]], and Alzheimer's disease have been reported.<ref>{{cite journal | vauthors = Luczynski P, Laule C, Hsiung GR, Moore GR, Tremlett H | title = Coexistence of Multiple Sclerosis and Alzheimer's disease: A review | journal = Multiple Sclerosis and Related Disorders | volume = 27 | pages = 232–238 | date = January 2019 | pmid = 30415025 | doi = 10.1016/j.msard.2018.10.109 }}</ref><ref>{{cite journal | vauthors = Londoño DP, Arumaithurai K, Constantopoulos E, Basso MR, Reichard RR, Flanagan EP, Keegan BM | title = Diagnosis of coexistent neurodegenerative dementias in multiple sclerosis | journal = Brain Communications | volume = 4 | issue = 4 | pages = fcac167 | date = 2022-07-04 | pmid = 35822102 | pmc = 9272064 | doi = 10.1093/braincomms/fcac167 }}</ref>

==== Other hypotheses ====
{{Anchor|Retrogenesis}}
{{See also|Cell cycle hypothesis of Alzheimer's disease|Ion channel hypothesis of Alzheimer's disease}}The association with [[celiac disease]] is unclear, with a 2019 study finding no increase in dementia overall in those with celiac disease while a 2018 review found an association with several types of dementia including Alzheimer's disease.<ref>{{cite journal | vauthors = Zis P, Hadjivassiliou M | title = Treatment of Neurological Manifestations of Gluten Sensitivity and Coeliac Disease | journal = Current Treatment Options in Neurology | volume = 21 | issue = 3 | pages = 10 | date = February 2019 | pmid = 30806821 | doi = 10.1007/s11940-019-0552-7 | s2cid = 73466457 | doi-access = free | title-link = doi }}</ref><ref name=MakhloufMesselmani2018>{{cite journal | vauthors = Makhlouf S, Messelmani M, Zaouali J, Mrissa R | title = Cognitive impairment in celiac disease and non-celiac gluten sensitivity: review of literature on the main cognitive impairments, the imaging and the effect of gluten free diet | journal = Acta Neurologica Belgica | volume = 118 | issue = 1 | pages = 21–27 | date = March 2018 | pmid = 29247390 | doi = 10.1007/s13760-017-0870-z | type = Review | s2cid = 3943047 }}</ref>

Studies have shown a potential link between infection with certain viruses and developing Alzheimer's disease later in life.<ref>{{cite journal | vauthors = Zhou L, Miranda-Saksena M, Saksena NK | title = Viruses and neurodegeneration | journal = Virology Journal | volume = 10 | issue = 1 | pages = 172 | date = May 2013 | pmid = 23724961 | pmc = 3679988 | doi = 10.1186/1743-422X-10-172 | doi-access = free }}</ref> Notably, a large scale study conducted on 6,245,282 patients has shown an increased risk of developing [[Alzheimer's disease and COVID-19|Alzheimer's disease following COVID-19 infection]] in cognitively normal individuals over 65.<ref>{{cite journal | vauthors = Gonzalez-Fernandez E, Huang J | title = Cognitive Aspects of COVID-19 | journal = Current Neurology and Neuroscience Reports | volume = 23 | issue = 9 | pages = 531–538 | date = September 2023 | pmid = 37490194 | doi = 10.1007/s11910-023-01286-y | s2cid = 260132167 }}</ref>

== Pathophysiology ==
[[File:Histopathology of Alzheimer's disease.jpg|thumb|upright=1.4|[[Histopathology|Histopathologic]] images of Alzheimer's disease, in the [[Hippocampus proper|CA3 area of the hippocampus]], showing an amyloid plaque (top right), neurofibrillary tangles (bottom left), and [[granulovacuolar degeneration|granulovacuolar degeneration bodies]] (bottom center)]]

===Neuropathology===

Alzheimer's disease is characterised by loss of [[neuron]]s and [[synapse]]s in the [[cerebral cortex]] and certain subcortical regions. This loss results in gross [[atrophy]] of the affected regions, including degeneration in the [[temporal lobe]] and [[parietal lobe]], and parts of the [[frontal cortex]] and [[cingulate gyrus]].<ref name=pmid12934968>{{cite journal | vauthors = Wenk GL | title = Neuropathologic changes in Alzheimer's disease | journal = The Journal of Clinical Psychiatry | volume = 64 | issue = Suppl 9 | pages = 7–10 | year = 2003 | pmid = 12934968 }}</ref> Degeneration is also present in [[brainstem]] nuclei particularly the [[locus coeruleus]] in the [[pons]].<ref>{{cite journal | vauthors = Braak H, Del Tredici K | title = Where, when, and in what form does sporadic Alzheimer's disease begin? | journal = Current Opinion in Neurology | volume = 25 | issue = 6 | pages = 708–714 | date = December 2012 | pmid = 23160422 | doi = 10.1097/WCO.0b013e32835a3432 }}</ref> Studies using [[magnetic resonance imaging|MRI]] and [[positron emission tomography|PET]] have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.<ref>{{cite journal | vauthors = Desikan RS, Cabral HJ, Hess CP, Dillon WP, Glastonbury CM, Weiner MW, Schmansky NJ, Greve DN, Salat DH, Buckner RL, Fischl B | title = Automated MRI measures identify individuals with mild cognitive impairment and Alzheimer's disease | journal = Brain | volume = 132 | issue = Pt 8 | pages = 2048–2057 | date = August 2009 | pmid = 19460794 | pmc = 2714061 | doi = 10.1093/brain/awp123 }}</ref><ref>{{cite journal |vauthors=Moan R |title=MRI Software Accurately IDs Preclinical Alzheimer's Disease |journal=Diagnostic Imaging |date=July 2009 |url=https://www.diagnosticimaging.com/view/mri-software-accurately-ids-preclinical-alzheimers-disease |access-date=21 February 2022 |archive-date=21 February 2022 |archive-url=https://web.archive.org/web/20220221050502/https://www.diagnosticimaging.com/view/mri-software-accurately-ids-preclinical-alzheimers-disease |url-status=live }}</ref>

Both [[Aβ]] [[amyloid plaques|plaques]] and [[neurofibrillary tangle]]s are clearly visible by [[microscopy]] in brains of those with Alzheimer's disease,<ref name=pmid15184601>{{cite journal | vauthors = Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J | title = The importance of neuritic plaques and tangles to the development and evolution of AD | journal = Neurology | volume = 62 | issue = 11 | pages = 1984–1989 | date = June 2004 | pmid = 15184601 | doi = 10.1212/01.WNL.0000129697.01779.0A | s2cid = 25017332 }}</ref> especially in the [[hippocampus]].<ref name=DeTureDickson2019>{{cite journal | vauthors = DeTure MA, Dickson DW | title = The neuropathological diagnosis of Alzheimer's disease | journal = Molecular Neurodegeneration | volume = 14 | issue = 1 | pages = 32 | date = August 2019 | pmid = 31375134 | pmc = 6679484 | doi = 10.1186/s13024-019-0333-5 | doi-access = free }}</ref> However, Alzheimer's disease may occur without neurofibrillary tangles in the [[neocortex]].<ref name=pmid15079014>{{cite journal | vauthors = Tiraboschi P, Sabbagh MN, Hansen LA, Salmon DP, Merdes A, Gamst A, Masliah E, Alford M, Thal LJ, Corey-Bloom J | title = Alzheimer disease without neocortical neurofibrillary tangles: "a second look" | journal = Neurology | volume = 62 | issue = 7 | pages = 1141–1147 | date = April 2004 | pmid = 15079014 | doi = 10.1212/01.wnl.0000118212.41542.e7 | s2cid = 22832110 }}</ref> Plaques are dense, mostly [[insoluble]] deposits of [[beta-amyloid]] peptide and [[Cell (biology)|cellular]] material outside and around [[Neuron|neurons]]. Neurofibrillary tangles are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of aging, the brains of people with Alzheimer's disease have a greater number of them in specific brain regions such as the [[temporal lobe]].<ref name=pmid8038565>{{cite journal | vauthors = Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH | title = Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital | journal = Cerebral Cortex | volume = 4 | issue = 2 | pages = 138–150 | year = 1994 | pmid = 8038565 | doi = 10.1093/cercor/4.2.138 }}</ref> [[Lewy body|Lewy bodies]] are not rare in the brains of people with Alzheimer's disease.<ref name=pmid11816795>{{cite journal | vauthors = Kotzbauer PT, Trojanowsk JQ, Lee VM | title = Lewy body pathology in Alzheimer's disease | journal = Journal of Molecular Neuroscience | volume = 17 | issue = 2 | pages = 225–232 | date = October 2001 | pmid = 11816795 | doi = 10.1385/JMN:17:2:225 | s2cid = 44407971 }}</ref>

===Biochemistry===
{{Main|Biochemistry of Alzheimer's disease}}

==== Amyloid beta ====
{{Multiple image|footer=Enzymes act on the amyloid-beta precursor protein and cut it into fragments. The beta-amyloid fragment is crucial in the formation of amyloid plaques in Alzheimer's disease.|image1=Amyloid 01big1.jpg|image2=Amyloid 02big1.jpg|image3=Amyloid 03big1.jpg}}

Alzheimer's disease has been identified as a [[protein misfolding disease]], a [[proteopathy]], caused by the accumulation of abnormally folded [[amyloid beta]] protein into amyloid plaques, and [[tau (protein)|tau protein]] into neurofibrillary tangles in the brain.<ref name=tzi/> Plaques are made up of small [[peptide]]s, 39–43&nbsp;[[amino acid]]s in length, called amyloid beta. Amyloid beta is a fragment from the larger [[amyloid-beta precursor protein]] (APP) a [[transmembrane protein]] that penetrates the [[Cell membrane|cell's membrane]]. APP is critical to neuron growth, survival, and post-injury repair.<ref name=tzi/> In Alzheimer's disease, [[gamma secretase]] and [[beta-secretase 1|beta secretase]] act together in a [[proteolysis|proteolytic]] process which causes APP to be divided into smaller fragments.<ref name=tzi/> Although commonly researched as neuronal proteins, APP and its processing enzymes are abundantly expressed by other brain cells. One of these fragments gives rise to [[Fibril|fibrils]] of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as amyloid plaques.<ref name=tzi/> Excitatory neurons are known to be the major producers of amyloid beta that contribute to major extracellular plaque deposition.<ref name=tzi/>

==== Phosphorylated tau ====
Alzheimer's disease is also considered a [[tauopathy]] due to abnormal aggregation of the [[tau protein]]. Every neuron has a [[cytoskeleton]], an internal support structure partly made up of structures called [[microtubules]]. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the [[axon]] and back. A protein called ''tau'' stabilises the microtubules when [[phosphorylation|phosphorylated]], and is therefore called a [[microtubule-associated protein]]. In Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.<ref name="pmid17604998">{{cite journal | vauthors = Hernández F, Avila J | title = Tauopathies | journal = Cellular and Molecular Life Sciences | volume = 64 | issue = 17 | pages = 2219–2233 | date = September 2007 | pmid = 17604998 | doi = 10.1007/s00018-007-7220-x | s2cid = 261121643 | pmc = 11136052 }}</ref> Pathogenic tau can also cause neuronal death through [[transposable element]] dysregulation.<ref>{{cite journal | vauthors = Sun W, Samimi H, Gamez M, Zare H, Frost B | title = Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies | journal = Nature Neuroscience | volume = 21 | issue = 8 | pages = 1038–1048 | date = August 2018 | pmid = 30038280 | pmc = 6095477 | doi = 10.1038/s41593-018-0194-1 }}</ref> [[Necroptosis]] has also been reported as a mechanism of cell death in brain cells affected with tau tangles.<ref>Balusu S, Horré K, Thrupp N, Craessaerts K, Snellinx A, Serneels L, T'Syen D, Chrysidou I, Arranz AM, Sierksma A, Simrén J, Karikari TK, Zetterberg H, Chen WT, Thal DR, Salta E, Fiers M, De Strooper B. MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease. ''Science''. 2023 Sep 15;381(6663):1176-1182. {{doi|10.1126/science.abp9556}} {{PMID|37708272}}</ref><ref>{{cite news |date=2023-09-15 |title=Scientists discover how brain cells die in Alzheimer's |language=en-GB |work=BBC News |url=https://www.bbc.com/news/health-66816268 |access-date=2023-09-27}}</ref>

===Disease mechanism===
Exactly how disturbances of production and aggregation of the beta-amyloid [[peptide]] give rise to the pathology of Alzheimer's disease is not known.<ref name=pmid17622778>{{cite journal | vauthors = Van Broeck B, Van Broeckhoven C, Kumar-Singh S | title = Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches | journal = Neuro-Degenerative Diseases | volume = 4 | issue = 5 | pages = 349–365 | year = 2007 | pmid = 17622778 | doi = 10.1159/000105156 | s2cid = 7949658 }}</ref><ref>{{cite journal | vauthors = Huang Y, Mucke L | title = Alzheimer mechanisms and therapeutic strategies | journal = Cell | volume = 148 | issue = 6 | pages = 1204–1222 | date = March 2012 | pmid = 22424230 | pmc = 3319071 | doi = 10.1016/j.cell.2012.02.040 }}</ref> The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated [[amyloid fibril]]s, which are believed to be the toxic form of the protein responsible for disrupting the cell's [[calcium]] ion [[homeostasis]], induces [[programmed cell death]] ([[apoptosis]]).<ref name=pmid2218531>{{cite journal | vauthors = Yankner BA, Duffy LK, Kirschner DA | title = Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides | journal = Science | volume = 250 | issue = 4978 | pages = 279–282 | date = October 1990 | pmid = 2218531 | doi = 10.1126/science.2218531 | bibcode = 1990Sci...250..279Y }}</ref> It is also known that A<sub>β</sub> selectively builds up in the [[Mitochondrion|mitochondria]] in the cells of Alzheimer's-affected brains, and it also inhibits certain [[enzyme]] functions and the utilisation of [[glucose]] by neurons.<ref name=pmid17424907>{{cite journal | vauthors = Chen X, Yan SD | title = Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer's disease | journal = IUBMB Life | volume = 58 | issue = 12 | pages = 686–694 | date = December 2006 | pmid = 17424907 | doi = 10.1080/15216540601047767 | s2cid = 85423830 }}</ref>

Iron dyshomeostasis is linked to disease progression, an iron-dependent form of regulated cell death called [[ferroptosis]] could be involved. Products of [[lipid peroxidation]] are also elevated in AD brain compared with controls.<ref>{{cite journal | vauthors = Ryan SK, Ugalde CL, Rolland AS, Skidmore J, Devos D, Hammond TR | title = Therapeutic inhibition of ferroptosis in neurodegenerative disease | journal = Trends in Pharmacological Sciences | volume = 44 | issue = 10 | pages = 674–688 | date = October 2023 | pmid = 37657967 | doi = 10.1016/j.tips.2023.07.007 | doi-access = free }}</ref>

Various inflammatory processes and [[cytokine]]s may also have a role in the pathology of Alzheimer's disease. [[Inflammation]] is a general marker of [[Tissue (biology)|tissue]] damage in any disease, and may be either secondary to tissue damage in Alzheimer's disease or a marker of an [[immunological response]].<ref name=pmid15681814>{{cite journal | vauthors = Greig NH, Mattson MP, Perry T, Chan SL, Giordano T, Sambamurti K, Rogers JT, Ovadia H, Lahiri DK | title = New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists | journal = Annals of the New York Academy of Sciences | volume = 1035 | pages = 290–315 | date = December 2004 | issue = 1 | pmid = 15681814 | doi = 10.1196/annals.1332.018 | bibcode = 2004NYASA1035..290G | s2cid = 84659695 | url = https://zenodo.org/record/1235888 | access-date = 19 July 2019 | archive-date = 3 June 2020 | archive-url = https://web.archive.org/web/20200603200152/https://zenodo.org/record/1235888/ | url-status = live }}</ref> There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.<ref>{{cite journal | vauthors = Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP | title = Neuroinflammation in Alzheimer's disease | journal = The Lancet. Neurology | volume = 14 | issue = 4 | pages = 388–405 | date = April 2015 | pmid = 25792098 | pmc = 5909703 | doi = 10.1016/S1474-4422(15)70016-5 }}</ref>

Alterations in the distribution of different [[neurotrophic factor]]s and in the expression of their receptors such as the [[brain-derived neurotrophic factor]] (BDNF) have been described in Alzheimer's disease.<ref>{{cite journal | vauthors = Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S | title = New insights into brain BDNF function in normal aging and Alzheimer disease | journal = Brain Research Reviews | volume = 59 | issue = 1 | pages = 201–220 | date = November 2008 | pmid = 18708092 | doi = 10.1016/j.brainresrev.2008.07.007 | hdl-access = free | s2cid = 6589846 | hdl = 10533/142174 }}</ref><ref>{{cite journal | vauthors = Schindowski K, Belarbi K, Buée L | title = Neurotrophic factors in Alzheimer's disease: role of axonal transport | journal = Genes, Brain and Behavior | volume = 7 | issue = Suppl 1 | pages = 43–56 | date = February 2008 | pmid = 18184369 | pmc = 2228393 | doi = 10.1111/j.1601-183X.2007.00378.x }}</ref>

==Diagnosis==
{{See also|Early-onset Alzheimer's disease#Diagnosis}}
[[File:PET Alzheimer.jpg|thumb|left|upright|[[Positron emission tomography|PET scan]] of the brain of a person with Alzheimer's disease showing a loss of function in the temporal lobe]]
Alzheimer's disease (AD) can only be definitively diagnosed with autopsy findings; in the absence of autopsy, clinical diagnoses of AD are "possible" or "probable", based on other findings.<ref name=Khan2020>{{cite journal |vauthors=Khan S, Barve KH, Kumar MS |title=Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer's Disease |journal=Curr Neuropharmacol |volume=18 |issue=11 |pages=1106–1125 |date=2020 |pmid=32484110 |pmc=7709159 |doi=10.2174/1570159X18666200528142429}}</ref><ref name=Gauthreaux2020>{{cite journal |vauthors = Gauthreaux K, Bonnett TA, Besser LM, Brenowitz WD, Teylan M, Mock C, Chen YC, Chan KC, Keene CD, Zhou XH, Kukull WA |title=Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy |journal=Journal of Neuropathology and Experimental Neurology |volume=79 |issue=5 |pages=465–473 |date=May 2020 |pmid=32186726 |pmc=7160616 |doi=10.1093/jnen/nlaa014 }}</ref><ref name=Sachdev2014 /> Up to 23% of those clinically diagnosed with AD may be misdiagnosed and may have pathology suggestive of another condition with symptoms that mimic those of AD.<ref name=Gauthreaux2020 />

AD is usually clinically diagnosed based on a person's [[medical history]], observations from friends or relatives, and behavioral changes. The presence of characteristic [[neuropsychology|neuropsychological]] changes with impairments in at least two cognitive domains that are severe enough to affect a person's functional abilities are required for the diagnosis. Domains that may be impaired include memory (most commonly impaired), language, [[executive function]], [[visuospatial]] functioning, or other areas of cognition. The neurocognitive changes must be a decline from a prior level of function and the diagnosis requires ruling out other common causes of neurocognitive decline.<ref name="Arvanitakis 2019" /><ref name=pmid17407994>{{cite journal | vauthors = Mendez MF | title = The accurate diagnosis of early-onset dementia | journal = International Journal of Psychiatry in Medicine | volume = 36 | issue = 4 | pages = 401–412 | year = 2006 | pmid = 17407994 | doi = 10.2190/Q6J4-R143-P630-KW41 | s2cid = 43715976 | url = https://zenodo.org/record/1236421 | access-date = 25 May 2020 | archive-date = 3 June 2020 | archive-url = https://web.archive.org/web/20200603200156/https://zenodo.org/record/1236421/ | url-status = live }}</ref><ref name=pmid17018549>{{cite journal | vauthors = Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J | title = Therapeutic approaches to Alzheimer's disease | journal = Brain | volume = 129 | issue = Pt 11 | pages = 2840–2855 | date = November 2006 | pmid = 17018549 | doi = 10.1093/brain/awl280 | doi-access = free | title-link = doi }}</ref> Advanced [[medical imaging]] with [[computed tomography]] (CT) or [[magnetic resonance imaging]] (MRI), and with [[single-photon emission computed tomography]] (SPECT) or [[positron emission tomography]] (PET), can be used to help exclude other cerebral pathology or subtypes of dementia.<ref>{{cite book |url=http://www.nice.org.uk/nicemedia/pdf/CG042quickrefguide.pdf |title=Dementia: Quick Reference Guide |publisher=(UK) [[National Institute for Health and Clinical Excellence]]|location=London|year=2006|isbn=978-1-84629-312-2|access-date=22 February 2008 |archive-url=https://web.archive.org/web/20080227161412/http://www.nice.org.uk/nicemedia/pdf/CG042quickrefguide.pdf|archive-date=27 February 2008|url-status=dead}}</ref> On MRI or CT, Alzheimer's disease usually shows a generalized or focal cortical atrophy, which may be asymmetric. Atrophy of the hippocampus is also commonly seen. Brain imaging commonly also shows cerebrovascular disease, most commonly previous strokes (small or large territory strokes), and this is thought to be a contributing cause of many cases of dementia (up to 46% cases of dementia also have cerebrovascular disease on imaging).<ref name="Arvanitakis 2019">{{cite journal |last1=Arvanitakis |first1=Zoe |last2=Shah |first2=Raj C. |last3=Bennett |first3=David A. |title=Diagnosis and Management of Dementia: Review |journal=JAMA |date=22 October 2019 |volume=322 |issue=16 |pages=1589–1599 |doi=10.1001/jama.2019.4782|pmid=31638686 |pmc=7462122 }}</ref> FDG-PET scan is not required for the diagnosis but it is sometimes used when standard testing is unclear. FDG-PET shows a bilateral, asymetric, temporal and parietal reduced activity.<ref name="Arvanitakis 2019" /> Advanced imaging may predict conversion from [[prodromal]] stages (mild cognitive impairment) to Alzheimer's disease.<ref name=Schroeter>{{cite journal | vauthors = Schroeter ML, Stein T, Maslowski N, Neumann J | title = Neural correlates of Alzheimer's disease and mild cognitive impairment: a systematic and quantitative meta-analysis involving 1351 patients | journal = NeuroImage | volume = 47 | issue = 4 | pages = 1196–1206 | date = October 2009 | pmid = 19463961 | pmc = 2730171 | doi = 10.1016/j.neuroimage.2009.05.037 }}</ref> FDA-approved [[Radiopharmaceuticals|radiopharmaceutical]] diagnostic agents used in PET for Alzheimer's disease are [[florbetapir]] (2012), [[flutemetamol]] (2013), [[florbetaben]] (2014), and [[Flortaucipir (18F)|flortaucipir]] (2020).<ref name=pmid33573211>{{cite journal | vauthors = Jie CV, Treyer V, Schibli R, Mu L | title = Tauvid: The First FDA-Approved PET Tracer for Imaging Tau Pathology in Alzheimer's Disease | journal = Pharmaceuticals | volume = 14 | issue = 2 | date = January 2021 | page = 110 | pmid = 33573211 | pmc = 7911942 | doi = 10.3390/ph14020110 | doi-access = free | title-link = doi }}</ref> Because many insurance companies in the United States do not cover this procedure, its use in clinical practice is largely limited to clinical trials {{as of|2018|lc=y}}.<ref name=Weller2018 />

[[Neuropsychological assessment|Assessment of intellectual functioning]] including memory testing can further characterise the state of the disease.<ref name=Knopman2021 /> Medical organizations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. Definitive diagnosis can only be confirmed with [[Autopsy|post-mortem]] evaluations when brain material is available and can be examined [[Histology|histologically]] for senile plaques and neurofibrillary tangles.<ref name=Weller2018 /><ref>{{cite journal | vauthors = Silva MV, Loures CM, Alves LC, de Souza LC, Borges KB, Carvalho MD | title = Alzheimer's disease: risk factors and potentially protective measures | journal = Journal of Biomedical Science | volume = 26 | issue = 1 | pages = 33 | date = May 2019 | pmid = 31072403 | pmc = 6507104 | doi = 10.1186/s12929-019-0524-y | doi-access = free }}</ref>

===Criteria===
There are three sets of criteria for the clinical diagnoses of the spectrum of Alzheimer's disease: the 2013 fifth edition of the ''[[Diagnostic and Statistical Manual of Mental Disorders]]'' ([[DSM-5]]); the [[National Institute on Aging]]-[[Alzheimer's Association]] (NIA-AA) definition as revised in 2011; and the International Working Group criteria as revised in 2010.<ref name=Atri2019>{{cite journal | vauthors = Atri A | title = The Alzheimer's Disease Clinical Spectrum: Diagnosis and Management | journal = The Medical Clinics of North America | volume = 103 | issue = 2 | pages = 263–293 | date = March 2019 | pmid = 30704681 | doi = 10.1016/j.mcna.2018.10.009 | s2cid = 73432842 | type = Review | doi-access = free }}</ref><ref name=Weller2018>{{cite journal | vauthors = Weller J, Budson A | title = Current understanding of Alzheimer's disease diagnosis and treatment | journal = F1000Research | volume = 7 | date = 2018 | page = 1161 | pmid = 30135715 | pmc = 6073093 | doi = 10.12688/f1000research.14506.1 | type = Review | doi-access = free }}</ref> 

Eight intellectual domains are most commonly impaired in AD—[[memory]], [[language]], [[perception|perceptual skills]], [[attention]], [[motor skill]]s, [[orientation (mental)|orientation]], [[problem solving]] and [[executive function]]al abilities, as listed in the fourth text revision of the DSM (DSM-IV-TR).<ref>{{cite book |title=Diagnostic and statistical manual of mental disorders: DSM-IV-TR |edition=4th Text Revision|publisher=American Psychiatric Association|year=2000|location=Washington, DC|isbn=978-0-89042-025-6}}</ref>

The [[DSM-5]] defines criteria for probable or possible AD for both major and mild neurocognitive disorder.<ref name=APA611>{{cite book|publisher=American Psychiatric Association|title=Diagnostic and statistical manual of mental disorders: DSM-5|year=2013|isbn=978-0-89042-555-8|location=Washington, D.C.|page=611}}</ref><ref>{{cite journal | vauthors = Sachs-Ericsson N, Blazer DG | title = The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment | journal = Aging & Mental Health | volume = 19 | issue = 1 | pages = 2–12 | date = January 2015 | pmid = 24914889 | doi = 10.1080/13607863.2014.920303 | s2cid = 46244321 }}</ref><ref name=Sachdev2014>{{cite journal | vauthors = Sachdev PS, Blacker D, Blazer DG, Ganguli M, Jeste DV, Paulsen JS, Petersen RC | title = Classifying neurocognitive disorders: the DSM-5 approach | journal = Nature Reviews. Neurology | volume = 10 | issue = 11 | pages = 634–642 | date = November 2014 | pmid = 25266297 | doi = 10.1038/nrneurol.2014.181 | s2cid = 20635070 | url = https://escholarship.org/uc/item/77g8t63q | access-date = 27 November 2021 | archive-date = 20 March 2022 | archive-url = https://web.archive.org/web/20220320083424/https://escholarship.org/uc/item/77g8t63q | url-status = live }}</ref> Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD.<ref name=APA611 /><ref>{{cite journal | vauthors = Stokin GB, Krell-Roesch J, Petersen RC, Geda YE | title = Mild Neurocognitive Disorder: An Old Wine in a New Bottle | journal = Harvard Review of Psychiatry | volume = 23 | issue = 5 | pages = 368–376 | date = 2015 | pmid = 26332219 | pmc = 4894762 | doi = 10.1097/HRP.0000000000000084 | type = Review }}</ref> For major neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if the individual has genetic evidence of AD<ref>{{cite book|url=https://www.taylorfrancis.com/books/edit/10.4324/9780203772287/psychopathology-psychotherapy-len-sperry-jon-carlson-jill-duba-sauerheber-jon-sperry|title=Psychopathology and Psychotherapy: DSM-5 Diagnosis, Case Conceptualization, and Treatment|journal=Taylor & Francis |year=2014|publisher=Routledge|isbn=978-0-203-77228-7|veditors=Sperry L, Carlson J, Sauerheber J, Sperry J|edition=3|location=New York|pages=342–343|doi=10.4324/9780203772287|access-date=16 November 2021|archive-date=16 November 2021|archive-url=https://web.archive.org/web/20211116213230/https://www.taylorfrancis.com/books/edit/10.4324/9780203772287/psychopathology-psychotherapy-len-sperry-jon-carlson-jill-duba-sauerheber-jon-sperry|url-status=live}}</ref> or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present.<ref>{{cite book|vauthors = Fink HA, Hemmy LS, Linskens EJ, Silverman PC, MacDonald R, McCarten JR, Talley KM, Desai PJ, Forte ML, Miller MA, Brasure M, Nelson VA, Taylor BC, Ng W, Ouellette JM, Greer NL, Sheets KM, Wilt TJ, Butler M |url=http://www.ncbi.nlm.nih.gov/books/NBK556556/|title=Diagnosis and Treatment of Clinical Alzheimer's-Type Dementia: A Systematic Review|date=2020|publisher=Agency for Healthcare Research and Quality (US)|series=AHRQ Comparative Effectiveness Reviews|location=Rockville (MD)|pmid=32369312|access-date=16 November 2021|archive-date=7 July 2023|archive-url=https://web.archive.org/web/20230707063441/https://www.ncbi.nlm.nih.gov/books/NBK556556/|url-status=live }}</ref> Otherwise, possible AD can be diagnosed as the diagnosis follows an atypical route.<ref>{{cite journal | vauthors = Stokin GB, Krell-Roesch J, Petersen RC, Geda YE | title = Mild Neurocognitive Disorder: An Old Wine in a New Bottle | journal = Harvard Review of Psychiatry | volume = 23 | issue = 5 | pages = 368–376 | date = September 2015 | pmid = 26332219 | pmc = 4894762 | doi = 10.1097/HRP.0000000000000084 | publisher = Wolters Kluwer Health }}</ref> For mild neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if there is genetic evidence, whereas possible AD can be met if all of the following are present: no genetic evidence, decline in both learning and memory, two or more cognitive deficits, and a functional disability not from another disorder.<ref name=APA611 /><ref>{{cite journal | vauthors = Bradfield NI, Ames D | title = Mild cognitive impairment: narrative review of taxonomies and systematic review of their prediction of incident Alzheimer's disease dementia | journal = BJPsych Bulletin | volume = 44 | issue = 2 | pages = 67–74 | date = April 2020 | pmid = 31724527 | pmc = 7283119 | doi = 10.1192/bjb.2019.77 | type = Review }}</ref>

The NIA-AA criteria are used mainly in research rather than in clinical assessments.<ref name=Vega2014>{{cite journal | vauthors = Vega JN, Newhouse PA | title = Mild cognitive impairment: diagnosis, longitudinal course, and emerging treatments | journal = Current Psychiatry Reports | volume = 16 | issue = 10 | pages = 490 | date = October 2014 | pmid = 25160795 | pmc = 4169219 | doi = 10.1007/s11920-014-0490-8 | publisher = SpringerLink }}</ref> They define AD through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia.<ref>{{cite journal | vauthors = Parnetti L, Chipi E, Salvadori N, D'Andrea K, Eusebi P | title = Prevalence and risk of progression of preclinical Alzheimer's disease stages: a systematic review and meta-analysis | journal = Alzheimer's Research & Therapy | volume = 11 | issue = 1 | pages = 7 | date = January 2019 | pmid = 30646955 | pmc = 6334406 | doi = 10.1186/s13195-018-0459-7 | publisher = Springer Nature | doi-access = free }}</ref><ref name=Jack2018>{{cite journal | vauthors = Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, Holtzman DM, Jagust W, Jessen F, Karlawish J, Liu E, Molinuevo JL, Montine T, Phelps C, Rankin KP, Rowe CC, Scheltens P, Siemers E, Snyder HM, Sperling R | title = NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease | journal = Alzheimer's & Dementia | volume = 14 | issue = 4 | pages = 535–562 | date = April 2018 | pmid = 29653606 | pmc = 5958625 | doi = 10.1016/j.jalz.2018.02.018  }}</ref> Diagnosis in the preclinical stage is complex and focuses on asymptomatic individuals;<ref name=Jack2018 /><ref>{{cite journal | vauthors = Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH | title = Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease | journal = Alzheimer's & Dementia | volume = 7 | issue = 3 | pages = 280–292 | date = May 2011 | pmid = 21514248 | pmc = 3220946 | doi = 10.1016/j.jalz.2011.03.003  }}</ref> the latter two stages describe individuals experiencing symptoms,<ref name=Jack2018 /> along with biomarkers,<ref>{{cite journal | vauthors = Cheng YW, Chen TF, Chiu MJ | title = From mild cognitive impairment to subjective cognitive decline: conceptual and methodological evolution | journal = Neuropsychiatric Disease and Treatment | volume = 13 | pages = 491–498 | date = 16 February 2017 | pmid = 28243102 | pmc = 5317337 | doi = 10.2147/NDT.S123428 | publisher = Dove Medical Press Limited | doi-access = free }}</ref> predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition.<ref name=Vega2014 /><ref name=Jack2018 /> The core clinical criteria itself rests on the presence of cognitive impairment<ref name=Jack2018 /> without the presence of comorbidities.<ref>{{cite journal | vauthors = Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH | title = The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease | journal = Alzheimer's & Dementia | volume = 7 | issue = 3 | pages = 270–279 | date = May 2011 | pmid = 21514249 | pmc = 3312027 | doi = 10.1016/j.jalz.2011.03.008  }}</ref><ref name=Chertkow2013 /> The third stage is divided into probable and possible AD dementia.<ref name=Chertkow2013>{{cite journal | vauthors = Chertkow H, Feldman HH, Jacova C, Massoud F | title = Definitions of dementia and predementia states in Alzheimer's disease and vascular cognitive impairment: consensus from the Canadian conference on diagnosis of dementia | journal = Alzheimer's Research & Therapy | volume = 5 | issue = Suppl 1 | pages = S2 | date = July 2013 | pmid = 24565215 | pmc = 3981054 | doi = 10.1186/alzrt198 | publisher = BMC | doi-access = free }}</ref> In probable AD dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction.<ref name=Chertkow2013 /> In possible AD dementia, another causal disease such as [[cerebrovascular disease]] is present.<ref name=Chertkow2013 />

===Techniques===
[[File:InterlockingPentagons.svg|right|thumb|[[Cognitive test]]s such as the mini–mental state examination (MMSE) can help in the diagnosis of Alzheimer's disease. In this test instructions are given to copy drawings like the one shown, remember some words, read, and subtract numbers serially.]]

[[Neuropsychological test]]s including [[cognitive test]]s such as the [[mini–mental state examination]] (MMSE), the [[Montreal Cognitive Assessment]] (MoCA) and the Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD.<ref name=Papadakis2021p1760>{{cite book|title=Current medical diagnosis & treatment |date=2021|vauthors=Papadakis MA, McPhee SJ, Rabow MW|isbn=978-1-260-46986-8|edition=Sixtieth |publisher= McGraw Hill|location=New York|page=1760|oclc=1195972209}}</ref> These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems;<ref name=Papadakis2021p1760 /> more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.<ref name=pmid1512391>{{cite journal | vauthors = Tombaugh TN, McIntyre NJ | title = The mini-mental state examination: a comprehensive review | journal = Journal of the American Geriatrics Society | volume = 40 | issue = 9 | pages = 922–935 | date = September 1992 | pmid = 1512391 | doi = 10.1111/j.1532-5415.1992.tb01992.x | s2cid = 25169596 }}</ref><ref name=pmid9987708>{{cite journal | vauthors = Pasquier F | title = Early diagnosis of dementia: neuropsychology | journal = Journal of Neurology | volume = 246 | issue = 1 | pages = 6–15 | date = January 1999 | pmid = 9987708 | doi = 10.1007/s004150050299 | s2cid = 2108587 }}</ref>

Further neurological examinations are crucial in the [[differential diagnosis]] of Alzheimer's disease and other diseases.<ref name=Waldemar2007 /> Interviews with family members are used in assessment; caregivers can supply important information on daily living abilities and on the decrease in the person's [[mental function]].<ref name=pmid16327345>{{cite journal | vauthors = Harvey PD, Moriarty PJ, Kleinman L, Coyne K, Sadowsky CH, Chen M, Mirski DF | title = The validation of a caregiver assessment of dementia: the Dementia Severity Scale | journal = Alzheimer Disease and Associated Disorders | volume = 19 | issue = 4 | pages = 186–194 | year = 2005 | pmid = 16327345 | doi = 10.1097/01.wad.0000189034.43203.60 | s2cid = 20238911 }}</ref> A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonly [[anosognosia|unaware of their deficits]].<ref name=pmid15738860>{{cite journal | vauthors = Antoine C, Antoine P, Guermonprez P, Frigard B | title = [Awareness of deficits and anosognosia in Alzheimer's disease] | language = fr | journal = L'Encéphale | volume = 30 | issue = 6 | pages = 570–577 | year = 2004 | pmid = 15738860 | doi = 10.1016/S0013-7006(04)95472-3 }}</ref> Many times, families have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.<ref name=pmid16197855>{{cite journal | vauthors = Cruz VT, Pais J, Teixeira A, Nunes B | title = [The initial symptoms of Alzheimer disease: caregiver perception] | language = pt | journal = Acta Médica Portuguesa | volume = 17 | issue = 6 | pages = 435–444 | year = 2004 | pmid = 16197855 }}</ref>

Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses.<ref name=Stern2020>{{cite book| vauthors = Stern SD, Cifu AS, Altkorn D |title=Symptom to diagnosis: an evidence-based guide|date=2020 |isbn=978-1-260-12111-7|edition=4th|location=New York | publisher = McGraw-Hill Medical |pages=209–210|oclc=1121597721}}</ref> Common supplemental tests include [[blood test]]s, [[thyroid function tests]], as well as tests to assess vitamin [[Vitamin B12|B12]] levels, rule out [[neurosyphilis]] and rule out metabolic problems (including tests for [[Assessment of kidney function|kidney function]], electrolyte levels and for [[diabetes]]).<ref name=Stern2020 /> MRI or CT scans might also be used to rule out other potential causes of the symptoms – including tumors or strokes.<ref name=Papadakis2021p1760 /> [[Delirium]] and depression can be common among individuals and are important to rule out.<ref>{{cite book|vauthors= Jha A, Mukhopadhaya K|title=Alzheimer's disease: diagnosis and treatment guide|date=2021|isbn=978-3-030-56739-2|publisher= Springer|location=Cham, Switzerland|page=32|oclc=1202472277}}</ref>

[[Psychological testing|Psychological tests]] for [[Major depressive disorder|depression]] are used, since depression can either be concurrent with AD (see [[Depression of Alzheimer disease]]), an early sign of cognitive impairment,<ref>{{cite journal | vauthors = Sun X, Steffens DC, Au R, Folstein M, Summergrad P, Yee J, Rosenberg I, Mwamburi DM, Qiu WQ | title = Amyloid-associated depression: a prodromal depression of Alzheimer disease? | journal = Archives of General Psychiatry | volume = 65 | issue = 5 | pages = 542–550 | date = May 2008 | pmid = 18458206 | pmc = 3042807 | doi = 10.1001/archpsyc.65.5.542 }}</ref> or even the cause.<ref name=pmid9153154>{{cite journal | vauthors = Geldmacher DS, Whitehouse PJ | title = Differential diagnosis of Alzheimer's disease | journal = Neurology | volume = 48 | issue = 5 Suppl 6 | pages = S2–S9 | date = May 1997 | pmid = 9153154 | doi = 10.1212/WNL.48.5_Suppl_6.2S | s2cid = 30018544 }}</ref><ref name=pmid17495754>{{cite journal | vauthors = Potter GG, Steffens DC | title = Contribution of depression to cognitive impairment and dementia in older adults | journal = The Neurologist | volume = 13 | issue = 3 | pages = 105–117 | date = May 2007 | pmid = 17495754 | doi = 10.1097/01.nrl.0000252947.15389.a9 | s2cid = 24569198 }}</ref>

Due to low accuracy, the C-PIB-PET scan is not recommended as an early diagnostic tool or for predicting the development of AD when people show signs of mild cognitive impairment (MCI).<ref>{{cite journal | vauthors = Zhang S, Smailagic N, Hyde C, Noel-Storr AH, Takwoingi Y, McShane R, Feng J | title = (11)C-PIB-PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI) | journal = The Cochrane Database of Systematic Reviews | issue = 7 | pages = CD010386 | date = July 2014 | volume = 2014 | pmid = 25052054 | pmc = 6464750 | doi = 10.1002/14651858.CD010386.pub2 }}</ref> The use of <sup>18</sup>F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is not supported by evidence.<ref>{{cite journal | vauthors = Smailagic N, Vacante M, Hyde C, Martin S, Ukoumunne O, Sachpekidis C | title = <sup>18</sup>F-FDG PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI) | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD010632 | date = January 2015 | issue = 1 | pmid = 25629415 | pmc = 7081123 | doi = 10.1002/14651858.CD010632.pub2 }}</ref>

==Prevention==
[[File:Honoré Daumier 032.jpg|right|thumb|Intellectual activities such as playing [[chess]] or regular social interaction have been linked to a reduced risk of Alzheimer's disease in epidemiological studies, although no causal relationship has been found.]]

There are no [[disease-modifying treatment]]s available to cure Alzheimer's disease and because of this, AD research has focused on interventions to prevent the onset and progression.<ref>{{cite journal | vauthors = Viña J, Sanz-Ros J | title = Alzheimer's disease: Only prevention makes sense | journal = European Journal of Clinical Investigation | volume = 48 | issue = 10 | pages = e13005 | date = October 2018 | pmid = 30028503 | doi = 10.1111/eci.13005 | s2cid = 51703879 | doi-access = free }}</ref> There is no evidence that supports any particular measure in preventing AD,<ref name=Knopman2021 /> and studies of measures to prevent the onset or progression have produced inconsistent results. Epidemiological studies have proposed relationships between an individual's likelihood of developing AD and modifiable factors, such as medications, lifestyle, and diet. There are some challenges in determining whether interventions for AD act as a primary prevention method, preventing the disease itself, or a secondary prevention method, identifying the early stages of the disease.<ref name=Hsu2017>{{cite journal |vauthors=Hsu D, Marshall GA |title=Primary and secondary prevention trials in Alzheimer disease: looking back, moving forward |journal=Curr Alzheimer Res |volume=14 |issue=4 |pages=426–440 |date=2017 |pmid=27697063 |pmc=5329133 |doi=10.2174/1567205013666160930112125 }}</ref> These challenges include duration of intervention, different stages of disease at which intervention begins, and lack of standardization of inclusion criteria regarding biomarkers specific for AD.<ref name=Hsu2017 /> Further research is needed to determine factors that can help prevent AD.<ref name=Hsu2017 />

===Medication===
Cardiovascular risk factors, such as [[hypercholesterolemia|hypercholesterolaemia]], [[hypertension]], [[diabetes]], and [[smoking]], are associated with a higher risk of onset and worsened course of AD.<ref name=pmid18299540>{{cite journal | vauthors = Patterson C, Feightner JW, Garcia A, Hsiung GY, MacKnight C, Sadovnick AD | title = Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease | journal = CMAJ | volume = 178 | issue = 5 | pages = 548–556 | date = February 2008 | pmid = 18299540 | pmc = 2244657 | doi = 10.1503/cmaj.070796 }}</ref><ref name=pmid17483665>{{cite journal | vauthors = Rosendorff C, Beeri MS, Silverman JM | title = Cardiovascular risk factors for Alzheimer's disease | journal = The American Journal of Geriatric Cardiology | volume = 16 | issue = 3 | pages = 143–149 | year = 2007 | pmid = 17483665 | doi = 10.1111/j.1076-7460.2007.06696.x }}</ref> The use of [[statin]]s to lower [[cholesterol]] may be of benefit in AD.<ref name=Chu>{{cite journal | vauthors = Chu CS, Tseng PT, Stubbs B, Chen TY, Tang CH, Li DJ, Yang WC, Chen YW, Wu CK, Veronese N, Carvalho AF, Fernandes BS, Herrmann N, Lin PY | title = Use of statins and the risk of dementia and mild cognitive impairment: A systematic review and meta-analysis | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 5804 | date = April 2018 | pmid = 29643479 | pmc = 5895617 | doi = 10.1038/s41598-018-24248-8 | bibcode = 2018NatSR...8.5804C }}</ref> [[Antihypertensive drug|Antihypertensive]] and [[Diabetes medication|antidiabetic]] medications in individuals without overt cognitive impairment may decrease the risk of dementia by influencing cerebrovascular [[pathology]].<ref name=Knopman2021 /><ref>{{cite journal |vauthors = Ungvari Z, Toth P, Tarantini S, Prodan CI, Sorond F, Merkely B, Csiszar A |title=Hypertension-induced cognitive impairment: from pathophysiology to public health |journal=Nature Reviews Nephrology |volume=17 |issue=10 |pages=639–654 |date=October 2021 |pmid=34127835 |pmc=8202227 |doi=10.1038/s41581-021-00430-6 }}</ref> More research is needed to examine the relationship with AD specifically; clarification of the direct role medications play versus other concurrent lifestyle changes (diet, exercise, smoking) is needed.<ref name=Knopman2021 />

Depression is associated with an increased risk for AD; management with antidepressant medications may provide a preventative measure.<ref name="Yu 1201–1209">{{cite journal |vauthors = Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Tan L, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B |title=Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials |journal=Journal of Neurology, Neurosurgery, and Psychiatry |volume=91 |issue=11 |pages=1201–1209 |date= November 2020 |pmid=32690803 |pmc=7569385 |doi=10.1136/jnnp-2019-321913 }}</ref>

Historically, long-term usage of [[non-steroidal anti-inflammatory drugs]] (NSAIDs) were thought to be associated with a reduced likelihood of developing AD as it reduces inflammation, but NSAIDs do not appear to be useful as a treatment.<ref name=Weller2018 /> Additionally, because women have a higher incidence of AD than men, it was once thought that [[estrogen deficiency]] during [[menopause]] was a risk factor, but there is a lack of evidence to show that [[Hormone replacement therapy (menopause)|hormone replacement therapy (HRT) in menopause]] decreases risk of cognitive decline.<ref>{{cite journal |vauthors=Lethaby A, Hogervorst E, Richards M, Yesufu A, Yaffe K |title=Hormone replacement therapy for cognitive function in postmenopausal women |journal=Cochrane Database Syst Rev |volume= 2008|issue=1 |pages=CD003122 |date=January 2008 |pmid=18254016 |pmc=6599876 |doi=10.1002/14651858.CD003122.pub2}}</ref>

===Lifestyle===
{{Further|Neurobiological effects of physical exercise}}
Certain lifestyle activities, such as physical and cognitive exercises, higher education and occupational attainment, cigarette smoking, stress, sleep, and the management of other comorbidities, including diabetes and hypertension, may affect the risk of developing AD.<ref name="Yu 1201–1209"/>

Physical exercise is associated with a decreased rate of dementia,<ref name=Cheng2016>{{cite journal |vauthors=Cheng ST |date=September 2016 |title=Cognitive Reserve and the Prevention of Dementia: the Role of Physical and Cognitive Activities |journal=Current Psychiatry Reports |type=Review |volume=18 |issue=9 |pages=85 |doi=10.1007/s11920-016-0721-2 |pmc=4969323 |pmid=27481112}}</ref> and is effective in reducing symptom severity in those with AD.<ref name=Farina2014>{{cite journal |vauthors=Farina N, Rusted J, Tabet N |date=January 2014 |title=The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review |journal=International Psychogeriatrics |type=Review |volume=26 |issue=1 |pages=9–18 |doi=10.1017/S1041610213001385 |pmid=23962667 |s2cid=24936334}}</ref> Memory and cognitive functions can be improved with aerobic exercises including brisk walking three times weekly for forty minutes.<ref name=Bernard2014>{{cite journal |vauthors = Barnard ND, Bush AI, Ceccarelli A, Cooper J, de Jager CA, Erickson KI, Fraser G, Kesler S, Levin SM, Lucey B, Morris MC, Squitti R |date=September 2014 |title=Dietary and lifestyle guidelines for the prevention of Alzheimer's disease |journal=Neurobiology of Aging |volume=35 |issue= Suppl 2|pages=S74–S78 |doi=10.1016/j.neurobiolaging.2014.03.033 |pmid=24913896 |s2cid=8265377|doi-access=free | title-link = doi |hdl=11343/52774 |hdl-access=free }}</ref> It may also induce [[neuroplasticity]] of the brain.<ref name=Bhatti20192>{{cite journal |vauthors=Bhatti GK, Reddy AP, Reddy PH, Bhatti JS |date=2019 |title=Lifestyle Modifications and Nutritional Interventions in Aging-Associated Cognitive Decline and Alzheimer's Disease |journal=Frontiers in Aging Neuroscience |type=Review |volume=11 |pages=369 |doi=10.3389/fnagi.2019.00369 |pmc=6966236 |pmid=31998117 |doi-access=free |title-link=doi}}</ref> Participating in mental exercises, such as reading, crossword puzzles, and chess have shown potential to be preventive.<ref name="Yu 1201–1209"/> Meeting the [[World Health Organization|WHO]] recommendations for physical activity is associated with a lower risk of AD.<ref>{{cite journal | vauthors = López-Ortiz S, Lista S, Valenzuela PL, Pinto-Fraga J, Carmona R, Caraci F, Caruso G, Toschi N, Emanuele E, Gabelle A, Nisticò R, Garaci F, Lucia A, Santos-Lozano A | title = Effects of physical activity and exercise interventions on Alzheimer's disease: an umbrella review of existing meta-analyses | journal = Journal of Neurology | date = November 2022 | volume = 270 | issue = 2 | pages = 711–725 | pmid = 36342524 | doi = 10.1007/s00415-022-11454-8 | s2cid = 253382289 }}</ref>

Higher education and occupational attainment, and participation in leisure activities, contribute to a reduced risk of developing AD,<ref name=Vina2018>{{cite journal |vauthors=Viña J, Sanz-Ros J |date=October 2018 |title=Alzheimer's disease: Only prevention makes sense |journal=European Journal of Clinical Investigation |type=Review |volume=48 |issue=10 |pages=e13005 |doi=10.1111/eci.13005 |pmid=30028503 |s2cid=51703879|doi-access=free }}</ref> or of delaying the onset of symptoms. This is compatible with the [[cognitive reserve]] theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations.<ref name=Vina2018 /> [[Education]] delays the onset of Alzheimer's disease syndrome without changing the duration of the disease.<ref name=Imtiaz2014>{{cite journal |vauthors=Imtiaz B, Tolppanen AM, Kivipelto M, Soininen H |date=April 2014 |title=Future directions in Alzheimer's disease from risk factors to prevention |journal=Biochemical Pharmacology |type=Review |volume=88 |issue=4 |pages=661–670 |doi=10.1016/j.bcp.2014.01.003 |pmid=24418410}}</ref>

Cessation in smoking may reduce risk of developing AD, specifically in those who carry the [[APOE E4|APOE ɛ4]] allele.<ref>{{cite journal |vauthors=Imtiaz B, Tolppanen AM, Kivipelto M, Soininen H |title=Future directions in Alzheimer's disease from risk factors to prevention |journal=Biochem Pharmacol |volume=88 |issue=4 |pages=661–70 |date=April 2014 |pmid=24418410 |doi=10.1016/j.bcp.2014.01.003}}</ref><ref name="Yu 1201–1209"/> The increased oxidative stress caused by smoking results in downstream inflammatory or neurodegenerative processes that may increase risk of developing AD.<ref>{{cite journal |vauthors=Kivipelto M, Mangialasche F, Ngandu T |title=Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease |journal=Nat Rev Neurol |volume=14 |issue=11 |pages=653–666 |date=November 2018 |pmid=30291317 |doi=10.1038/s41582-018-0070-3 |s2cid=52925352 }}</ref> Avoidance of smoking, counseling and pharmacotherapies to quit smoking are used, and avoidance of environmental tobacco smoke is recommended.<ref name="Yu 1201–1209"/>

Alzheimer's disease is associated with [[Sleep disorder|sleep disorders]] but the precise relationship is unclear.<ref name=Borges2019>{{cite journal |vauthors=Borges CR, Poyares D, Piovezan R, Nitrini R, Brucki S |title=Alzheimer's disease and sleep disturbances: a review |journal=Arq Neuropsiquiatr |volume=77 |issue=11 |pages=815–824 |date=November 2019 |pmid=31826138 |doi=10.1590/0004-282X20190149 |s2cid=209327994 |doi-access=free }}</ref><ref name=Uddin2020>{{cite journal |vauthors = Uddin MS, Tewari D, Mamun AA, Kabir MT, Niaz K, Wahed MI, Barreto GE, Ashraf GM |title=Circadian and sleep dysfunction in Alzheimer's disease |journal=Ageing Research Reviews |volume=60 |pages=101046 |date=July 2020 |pmid=32171783 |doi=10.1016/j.arr.2020.101046|s2cid=212729131 }}</ref> It was once thought that as people get older, the risk of developing sleep disorders and AD independently increase, but research is examining whether sleep disorders may increase the prevalence of AD.<ref name=Borges2019 /> One theory is that the mechanisms to increase clearance of toxic substances, including [[Amyloid beta|Aβ]], are active during sleep.<ref name=Borges2019 /><ref>{{cite journal |vauthors=Rasmussen MK, Mestre H, Nedergaard M |title=The glymphatic pathway in neurological disorders |journal=Lancet Neurol |volume=17 |issue=11 |pages=1016–1024 |date=November 2018 |pmid=30353860 |pmc=6261373 |doi=10.1016/S1474-4422(18)30318-1}}</ref> With decreased sleep, a person is increasing Aβ production and decreasing Aβ clearance, resulting in Aβ accumulation.<ref>{{cite journal |vauthors=Irwin MR, Vitiello MV |title=Implications of sleep disturbance and inflammation for Alzheimer's disease dementia |journal=Lancet Neurol |volume=18 |issue=3 |pages=296–306 |date=March 2019 |pmid=30661858 |doi=10.1016/S1474-4422(18)30450-2 |s2cid=58546748 }}</ref><ref name=Borges2019 /><ref name=Uddin2020 /> Receiving adequate sleep (approximately 7–8 hours) every night has become a potential lifestyle intervention to prevent the development of AD.<ref name="Yu 1201–1209"/>

Stress is a risk factor for the development of AD.<ref name="Yu 1201–1209"/> The mechanism by which stress predisposes someone to development of AD is unclear, but it is suggested that lifetime stressors may affect a person's [[epigenome]], leading to an overexpression or under expression of specific genes.<ref>{{cite journal |vauthors = Hampel H, Vergallo A, Aguilar LF, Benda N, Broich K, Cuello AC, Cummings J, Dubois B, Federoff HJ, Fiandaca M, Genthon R, Haberkamp M, Karran E, Mapstone M, Perry G, Schneider LS, Welikovitch LA, Woodcock J, Baldacci F, Lista S |title=Precision pharmacology for Alzheimer's disease |journal=Pharmacological Research |volume=130 |issue= |pages=331–365 |date=April 2018 |pmid=29458203 |pmc=8505114 |doi=10.1016/j.phrs.2018.02.014 }}</ref> Although the relationship of stress and AD is unclear, strategies to reduce stress and relax the mind may be helpful strategies in preventing the progression or Alzheimer's disease.<ref>{{cite journal |vauthors = Chen Y, Zhang J, Zhang T, Cao L, You Y, Zhang C, Liu X, Zhang Q |title=Meditation treatment of Alzheimer disease and mild cognitive impairment: A protocol for systematic review |journal=Medicine |volume=99 |issue=10 |pages=e19313 |date=March 2020 |pmid=32150066 |pmc=7478420 |doi=10.1097/MD.0000000000019313 }}</ref> Meditation, for instance, is a helpful lifestyle change to support cognition and well-being, though further research is needed to assess long-term effects.<ref name=Bhatti20192 />

==Management==
There is no cure for AD;<ref>{{cite journal | vauthors = Winkelman MJ, Szabo A, Frecska E | title = The potential of psychedelics for the treatment of Alzheimer's disease and related dementias | journal = European Neuropsychopharmacology | volume = 76 | pages = 3–16 | date = November 2023 | pmid = 37451163 | doi = 10.1016/j.euroneuro.2023.07.003 | hdl-access = free | doi-access = free | hdl = 10852/108211 }}</ref> available treatments offer relatively small symptomatic benefits but remain [[palliative care|palliative]] in nature.<ref name=Breijyeh2020 /><ref>{{cite book|title=Blueprints neurology|date=2019|vauthors= Drislane F, Hovauimian A, Tarulli A, Boegle AK, McIiduff C, Caplan LR |isbn=978-1-4963-8739-4|edition=Fifth|publisher= Wolters Kluwer|location=Philadelphia|page=146|oclc=1048659425}}</ref> Treatments can be divided into pharmaceutical, psychosocial, and caregiving.

===Pharmaceutical===
[[File:Donepezil 1EVE.png|right|thumb|Three-dimensional [[molecular model]] of [[donepezil]], an [[acetylcholinesterase inhibitor]] used in the treatment of Alzheimer's disease symptoms]]
[[File:Memantine.svg|right|thumb|upright|Molecular structure of [[memantine]], a medication approved for advanced Alzheimer's disease symptoms]]
Medications used to treat the cognitive symptoms of AD rather than the underlying cause include: four [[acetylcholinesterase inhibitor]]s ([[tacrine]], [[rivastigmine]], [[galantamine]], and [[donepezil]]) and [[memantine]], an [[NMDA receptor antagonist]]. The acetylcholinesterase inhibitors are intended for those with mild to severe AD, whereas memantine is intended for those with moderate or severe Alzheimer's disease.<ref name=Weller2018 /> The benefit from their use is small.<ref name=Birks2018 /><ref>{{cite journal | vauthors = Fink HA, Linskens EJ, MacDonald R, Silverman PC, McCarten JR, Talley KM, Forte ML, Desai PJ, Nelson VA, Miller MA, Hemmy LS, Brasure M, Taylor BC, Ng W, Ouellette JM, Sheets KM, Wilt TJ, Butler M |title = Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia | journal = Annals of Internal Medicine | volume = 172 | issue = 10 | pages = 656–668 | date = May 2020 | pmid = 32340037 | doi = 10.7326/M19-3887 | s2cid = 216595473 }}</ref><ref name=Berkowitz236>{{cite book|vauthors=Berkowitz A|title=Clinical neurology and neuroanatomy: a localization-based approach|date=2017|isbn=978-1-259-83440-0|publisher= McGraw Hill|location=New York|page=236|oclc=948547621}}</ref><ref name=Simon2018p111 />

Reduction in the activity of the [[cholinergic]] neurons is a well-known feature of AD.<ref name=pmid8534419>{{cite journal | vauthors = Geula C, Mesulam MM | title = Cholinesterases and the pathology of Alzheimer disease | journal = Alzheimer Disease and Associated Disorders | volume = 9 | issue = Suppl 2 | pages = 23–28 | year = 1995 | pmid = 8534419 | doi = 10.1097/00002093-199501002-00005 }}</ref> Acetylcholinesterase inhibitors are employed to reduce the rate at which [[acetylcholine]] (ACh) is broken down, thereby increasing the concentration of ACh in the brain and combating the loss of ACh caused by the death of cholinergic neurons.<ref name=pmid11105732>{{cite journal | vauthors = Stahl SM | title = The new cholinesterase inhibitors for Alzheimer's disease, Part 2: illustrating their mechanisms of action | journal = The Journal of Clinical Psychiatry | volume = 61 | issue = 11 | pages = 813–814 | date = November 2000 | pmid = 11105732 | doi = 10.4088/JCP.v61n1101 | doi-access = free }}</ref> There is evidence for the efficacy of these medications in mild to moderate AD,<ref name=pmid16437532>{{cite journal | vauthors = Birks J | title = Cholinesterase inhibitors for Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD005593 | date = January 2006 | volume = 2016 | pmid = 16437532 | doi = 10.1002/14651858.CD005593 | pmc = 9006343 | veditors = Birks J }}</ref><ref name=Birks2018>{{cite journal | vauthors = Birks JS, Harvey RJ | title = Donepezil for dementia due to Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 6 | pages = CD001190 | date = June 2018 | pmid = 29923184 | pmc = 6513124 | doi = 10.1002/14651858.CD001190.pub3 }}</ref> and some evidence for their use in the advanced stage.<ref name=Birks2018 /> The use of these drugs in [[mild cognitive impairment]] has not shown any effect in a delay of the onset of Alzheimer's disease.<ref name=pmid18044984>{{cite journal | vauthors = Raschetti R, Albanese E, Vanacore N, Maggini M | title = Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials | journal = PLOS Medicine | volume = 4 | issue = 11 | pages = e338 | date = November 2007 | pmid = 18044984 | pmc = 2082649 | doi = 10.1371/journal.pmed.0040338 | doi-access = free }}</ref> The most common [[adverse drug reaction|side effects]] are [[nausea]] and [[vomiting]], both of which are linked to cholinergic excess. These side effects arise in approximately 10–20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses.<ref>{{cite book |vauthors=Alldredge BK, Corelli RL, Ernst ME, Guglielmo BJ, Jacobson PA, Kradjan WA, Williams BR |title=Applied therapeutics : the clinical use of drugs |date=2013 |publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Baltimore|isbn=978-1-60913-713-7|page=2385|edition=10th}}</ref> Less common secondary effects include muscle [[cramp]]s, decreased [[heart rate]] ([[bradycardia]]), decreased [[appetite]] and weight, and increased [[gastric acid]] production.<ref name=pmid16437532 />

[[Glutamate (neurotransmitter)|Glutamate]] is an excitatory [[neurotransmitter]] of the [[nervous system]], although excessive amounts in the [[brain]] can lead to [[Cell (biology)|cell]] death through a process called [[excitotoxicity]] which consists of the overstimulation of glutamate [[Receptor (biochemistry)|receptors]]. Excitotoxicity occurs not only in AD, but also in other neurological diseases such as [[Parkinson's disease]] and [[multiple sclerosis]].<ref name=pmid16424917>{{cite journal | vauthors = Lipton SA | title = Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond | journal = Nature Reviews. Drug Discovery | volume = 5 | issue = 2 | pages = 160–170 | date = February 2006 | pmid = 16424917 | doi = 10.1038/nrd1958 | s2cid = 21379258 }}</ref> [[Memantine]] is a noncompetitive [[NMDA receptor antagonist]] first used as an anti-[[influenza]] agent. It acts on the [[glutamatergic system]] by blocking [[NMDA receptor]]s and inhibiting their overstimulation by glutamate.<ref name=pmid16424917 /><ref>{{cite web |url=https://www.nlm.nih.gov/medlineplus/druginfo/meds/a604006.html |title=Memantine |access-date=3 February 2010|date=4 January 2004|publisher=US National Library of Medicine (Medline) |archive-url=https://web.archive.org/web/20100222203921/https://www.nlm.nih.gov/medlineplus/druginfo/meds/a604006.html |archive-date=22 February 2010 | url-status=live
}}</ref> Memantine has been shown to have a small benefit in the treatment of moderate to severe AD.<ref>{{cite journal | vauthors = McShane R, Westby MJ, Roberts E, Minakaran N, Schneider L, Farrimond LE, Maayan N, Ware J, Debarros J | title = Memantine for dementia | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 3 | pages = CD003154 | date = March 2019 | pmid = 30891742 | pmc = 6425228 | doi = 10.1002/14651858.CD003154.pub6 }}</ref> Reported adverse events with memantine are infrequent and mild, including [[hallucination]]s, [[confusion]], [[dizziness]], [[headache]] and [[fatigue]].<ref>{{cite web | title=Namenda- memantine hydrochloride tablet Namenda- memantine hydrochloride kit | website=DailyMed | date=15 November 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9f27baf-aa2a-443a-9ef5-e002d23407ba | access-date=20 February 2022 | archive-date=27 January 2022 | archive-url=https://web.archive.org/web/20220127063519/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9f27baf-aa2a-443a-9ef5-e002d23407ba | url-status=live }}</ref><ref>{{cite web | title=Namenda XR- memantine hydrochloride capsule, extended release Namenda XR- memantine hydrochloride kit | website=DailyMed | date=15 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=710f523f-0158-4639-8ce7-57598247d48c | access-date=20 February 2022 | archive-date=21 February 2022 | archive-url=https://web.archive.org/web/20220221050503/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=710f523f-0158-4639-8ce7-57598247d48c | url-status=live }}</ref> The combination of memantine and donepezil<ref>{{cite web | title=Namzaric- memantine hydrochloride and donepezil hydrochloride capsule Namzaric- memantine hydrochloride and donepezil hydrochloride kit | website=DailyMed | date=22 January 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=90fedc32-19e5-480c-afc6-f35a5cf4b9aa | access-date=20 February 2022 | archive-date=20 January 2022 | archive-url=https://web.archive.org/web/20220120050522/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=90fedc32-19e5-480c-afc6-f35a5cf4b9aa | url-status=live }}</ref> has been shown to be "of [[Statistical significance|statistically significant]] but clinically marginal effectiveness".<ref name=pmid18316756>{{cite journal | vauthors = Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, Booker L, Oremus M | title = Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline | journal = Annals of Internal Medicine | volume = 148 | issue = 5 | pages = 379–397 | date = March 2008 | pmid = 18316756 | doi = 10.7326/0003-4819-148-5-200803040-00009 | s2cid = 22235353 }}</ref>

An extract of ''[[Ginkgo biloba]]'' known as ''EGb 761'' has been used for treating AD and other neuropsychiatric disorders.<ref name=Kandia>{{cite journal | vauthors = Kandiah N, Ong PA, Yuda T, Ng LL, Mamun K, Merchant RA, Chen C, Dominguez J, Marasigan S, Ampil E, Nguyen VT, Yusoff S, Chan YF, Yong FM, Krairit O, Suthisisang C, Senanarong V, Ji Y, Thukral R, Ihl R | title = Treatment of dementia and mild cognitive impairment with or without cerebrovascular disease: Expert consensus on the use of Ginkgo biloba extract, EGb 761 | journal = CNS Neuroscience & Therapeutics | volume = 25 | issue = 2 | pages = 288–298 | date = February 2019 | pmid = 30648358 | pmc = 6488894 | doi = 10.1111/cns.13095 }}</ref> Its use is approved throughout Europe.<ref name=McKeage>{{cite journal | vauthors = McKeage K, Lyseng-Williamson KA | title = ''Ginkgo biloba'' extract EGb 761 in the symptomatic treatment of mild-to-moderate dementia: a profile of its use | journal = Drugs & Therapy Perspectives | volume = 34 | issue = 8 | pages = 358–366 | date = 2018 | pmid = 30546253 | pmc = 6267544 | doi = 10.1007/s40267-018-0537-8 }}</ref> The World Federation of Biological Psychiatry guidelines lists EGb 761 with the same weight of evidence (level B) given to acetylcholinesterase inhibitors and memantine. EGb 761 is the only one that showed improvement of symptoms in both AD and vascular dementia. EGb 761 may have a role either on its own or as an add-on if other therapies prove ineffective.<ref name=Kandia /> A 2016 review concluded that the quality of evidence from clinical trials on ''Ginkgo biloba'' has been insufficient to warrant its use for treating AD.<ref name=yang>{{cite journal | vauthors = Yang G, Wang Y, Sun J, Zhang K, Liu J | title = Ginkgo Biloba for Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials | journal = Current Topics in Medicinal Chemistry | volume = 16 | issue = 5 | pages = 520–528 | date = 22 October 2015 | pmid = 26268332 | doi = 10.2174/1568026615666150813143520 }}</ref>

[[Atypical antipsychotic]]s are modestly useful in reducing [[aggression]] and [[psychosis]] in people with AD, but their advantages are offset by serious adverse effects, such as [[stroke]], [[Extrapyramidal symptoms|movement difficulties]] or cognitive decline.<ref>{{cite journal | vauthors = Ballard C, Waite J | title = The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003476 | date = January 2006 | pmid = 16437455 | doi = 10.1002/14651858.CD003476.pub2 | veditors = Ballard CG | pmc = 11365591 }}</ref> When used in the long-term, they have been shown to associate with increased mortality.<ref name=pmid19138567>{{cite journal | vauthors = Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, Gill R, Juszczak E, Yu LM, Jacoby R | title = The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial | journal = The Lancet. Neurology | volume = 8 | issue = 2 | pages = 151–157 | date = February 2009 | pmid = 19138567 | doi = 10.1016/S1474-4422(08)70295-3 | s2cid = 23000439}} See [https://web.archive.org/web/20170803221631/https://medicalxpress.com/news/2009-01-antipsychotic-drugs-death-alzheimer-patients.html lay summary], January 2009.</ref> They are recommended in dementia only after first line therapies such as behavior modification have failed, and due to the risk of adverse effects, they should be used for the shortest amount of time possible.<ref name="Arvanitakis 2019" /> Stopping antipsychotic use in this group of people appears to be safe.<ref>{{cite journal | vauthors = Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AI, van Driel ML, Christiaens T | title = Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 3 | pages = CD007726 | date = March 2013 | pmid = 23543555 | doi = 10.1002/14651858.CD007726.pub2 | hdl-access = free | hdl = 1854/LU-3109108 }}</ref>

===Psychosocial===
[[Psychosocial]] interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior-, emotion-, cognition- or stimulation-oriented approaches.{{update after|2022|2|16}}<ref name=pracGuideAPA>{{update after|2022|2|16}} {{cite journal | vauthors = Rabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS, Tariot PN, Blass DM, McIntyre JS, Charles SC, Anzia DJ, Cook IA, Finnerty MT, Johnson BR, Nininger JE, Schneidman B, Summergrad P, Woods SM, Berger J, Cross CD, Brandt HA, Margolis PM, Shemo JP, Blinder BJ, Duncan DL, Barnovitz MA, Carino AJ, Freyberg ZZ, Gray SH, Tonnu T, Kunkle R, Albert AB, Craig TJ, Regier DA, Fochtmann LJ | title = American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. Second edition | journal = The American Journal of Psychiatry | volume = 164 | issue = 12 Suppl | pages = 5–56 | date = December 2007 | pmid = 18340692 | collaboration = Steering Committee on Practice Guidelines }}</ref>

[[Behavior modification|Behavioral interventions]] attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in improving overall functioning,<ref name=pmid16323385>{{cite journal | vauthors = Bottino CM, Carvalho IA, Alvarez AM, Avila R, Zukauskas PR, Bustamante SE, Andrade FC, Hototian SR, Saffi F, Câmargo CH | title = Cognitive rehabilitation combined with drug treatment in Alzheimer's disease patients: a pilot study | journal = Clinical Rehabilitation | volume = 19 | issue = 8 | pages = 861–869 | date = December 2005 | pmid = 16323385 | doi = 10.1191/0269215505cr911oa | s2cid = 21290731 }}</ref> but can help to reduce some specific problem behaviors, such as [[Urinary incontinence|incontinence]].<ref name=pmid11342679>{{cite journal | vauthors = Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, Mohs RC, Thal LJ, Whitehouse PJ, DeKosky ST, Cummings JL | author-link1= Rachelle Doody| title = Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 56 | issue = 9 | pages = 1154–1166 | date = May 2001 | pmid = 11342679 | doi = 10.1212/WNL.56.9.1154 | s2cid = 10711725 | doi-access = free | title-link = doi }}</ref> There is a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.<ref name=pmid17253573>{{cite journal | vauthors = Hermans DG, Htay UH, McShane R | title = Non-pharmacological interventions for wandering of people with dementia in the domestic setting | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD005994 | date = January 2007 | volume = 2010 | pmid = 17253573 | pmc = 6669244 | doi = 10.1002/14651858.CD005994.pub2 }}</ref><ref name=pmid17096455>{{cite journal | vauthors = Robinson L, Hutchings D, Dickinson HO, Corner L, Beyer F, Finch T, Hughes J, Vanoli A, Ballard C, Bond J | title = Effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia: a systematic review | journal = International Journal of Geriatric Psychiatry | volume = 22 | issue = 1 | pages = 9–22 | date = January 2007 | pmid = 17096455 | doi = 10.1002/gps.1643 | s2cid = 45660235 }}</ref> [[Music therapy]] is effective in reducing behavioral and psychological symptoms.<ref>{{cite journal | vauthors = Abraha I, Rimland JM, Trotta FM, Dell'Aquila G, Cruz-Jentoft A, Petrovic M, Gudmundsson A, Soiza R, O'Mahony D, Guaita A, Cherubini A | title = Systematic review of systematic reviews of non-pharmacological interventions to treat behavioural disturbances in older patients with dementia. The SENATOR-OnTop series | journal = BMJ Open | volume = 7 | issue = 3 | pages = e012759 | date = March 2017 | pmid = 28302633 | pmc = 5372076 | doi = 10.1136/bmjopen-2016-012759 }}</ref>

Emotion-oriented interventions include [[reminiscence therapy]], [[validation therapy]], supportive [[psychotherapy]], [[sensory integration therapy|sensory integration]], also called [[snoezelen]], and [[simulated presence therapy]]. A Cochrane review has found no evidence that this is effective.<ref>{{cite journal | vauthors = Chung JC, Lai CK, Chung PM, French HP | title = Snoezelen for dementia | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD003152 | date = 2002 | volume = 2010 | pmid = 12519587 | doi = 10.1002/14651858.CD003152 | pmc = 9002239 }}</ref> Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. A 2018 review of the effectiveness of RT found that effects were inconsistent, small in size and of doubtful clinical significance, and varied by setting.<ref>{{cite journal | vauthors = Woods B, O'Philbin L, Farrell EM, Spector AE, Orrell M | title = Reminiscence therapy for dementia | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 3 | pages = CD001120 | date = March 2018 | pmid = 29493789 | pmc = 6494367 | doi = 10.1002/14651858.CD001120.pub3 }}</ref> Simulated presence therapy (SPT) is based on [[Attachment theory|attachment theories]] and involves playing a recording with voices of the closest relatives of the person with AD. There is partial evidence indicating that SPT may reduce [[challenging behavior]]s.<ref name=pmid19023729>{{cite journal | vauthors = Zetteler J | title = Effectiveness of simulated presence therapy for individuals with dementia: a systematic review and meta-analysis | journal = Aging & Mental Health | volume = 12 | issue = 6 | pages = 779–785 | date = November 2008 | pmid = 19023729 | doi = 10.1080/13607860802380631 | s2cid = 39529938 }}</ref>

The aim of cognition-oriented treatments, which include reality orientation and [[Rehabilitation (neuropsychology)|cognitive retraining]], is the reduction of [[cognitive deficit]]s. Reality orientation consists of the presentation of information about time, place, or person to ease the understanding of the person about its surroundings and his or her place in them. On the other hand, cognitive retraining tries to improve impaired capacities by exercising mental abilities. Both have shown some efficacy improving cognitive capacities.<ref name=pmid12948999>{{cite journal | vauthors = Spector A, Thorgrimsen L, Woods B, Royan L, Davies S, Butterworth M, Orrell M | title = Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial | journal = The British Journal of Psychiatry | volume = 183 | issue = 3 | pages = 248–254 | date = September 2003 | pmid = 12948999 | doi = 10.1192/bjp.183.3.248 | doi-access = free | title-link = doi }}</ref>

Stimulation-oriented treatments include [[Art therapy|art]], [[Music therapy for Alzheimer's disease|music]] and [[Animal-assisted therapy|pet]] therapies, [[Physical therapy|exercise]], and any other kind of [[Recreational therapy|recreational activities]]. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the change in the person's routine.<ref name=pracGuideAPA />

===Caregiving===
{{Further|Caring for people with dementia|Palliative care}}
Since AD has no cure and it gradually renders people incapable of tending to their own needs, caregiving is essentially the treatment and must be carefully managed over the course of the disease.

During the early and moderate stages, modifications to the living environment and lifestyle can increase [[patient safety|safety]] and reduce caretaker burden.<ref name=pmid11220813>{{cite journal | vauthors = Gitlin LN, Corcoran M, Winter L, Boyce A, Hauck WW | title = A randomized, controlled trial of a home environmental intervention: effect on efficacy and upset in caregivers and on daily function of persons with dementia | journal = The Gerontologist | volume = 41 | issue = 1 | pages = 4–14 | date = February 2001 | pmid = 11220813 | doi = 10.1093/geront/41.1.4 | doi-access = free | title-link = doi }}</ref><ref name=pmid15860476>{{cite journal | vauthors = Gitlin LN, Hauck WW, Dennis MP, Winter L | title = Maintenance of effects of the home environmental skill-building program for family caregivers and individuals with Alzheimer's disease and related disorders | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 60 | issue = 3 | pages = 368–374 | date = March 2005 | pmid = 15860476 | doi = 10.1093/gerona/60.3.368 | doi-access = free | title-link = doi }}</ref> Examples of such modifications are the adherence to simplified routines, the placing of safety locks, the labeling of household items to cue the person with the disease or the use of modified daily life objects.<ref name=pracGuideAPA /><ref>{{cite web |url=http://www.alz.org/Health/Treating/agitation.asp |title=Treating Behavioral and Psychiatric Symptoms |year=2006|access-date=25 September 2006|publisher=Alzheimer's Association |archive-url=https://web.archive.org/web/20060925112503/http://www.alz.org/Health/Treating/agitation.asp|archive-date=25 September 2006}}</ref><ref name=pmid15297089>{{cite journal | vauthors = Dunne TE, Neargarder SA, Cipolloni PB, Cronin-Golomb A | title = Visual contrast enhances food and liquid intake in advanced Alzheimer's disease | journal = Clinical Nutrition | volume = 23 | issue = 4 | pages = 533–538 | date = August 2004 | pmid = 15297089 | doi = 10.1016/j.clnu.2003.09.015 }}</ref> If eating becomes problematic, food will need to be prepared in smaller pieces or even [[purée]]d.<ref>{{cite book |vauthors=Dudek SB |title=Nutrition Essentials for Nursing Practice |publisher=Lippincott Williams & Wilkins|location=Hagerstown, Maryland|year=2007|page=360|isbn=978-0-7817-6651-7 |url=https://books.google.com/books?id=01zo6yf0IUEC&pg=PA360 |access-date=19 August 2008}}</ref> When [[Dysphagia|swallowing difficulties]] arise, the use of [[feeding tube]]s may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members.<ref name=pmid16415742>{{cite journal | vauthors = Dennehy C | title = Analysis of patients' rights: dementia and PEG insertion | journal = British Journal of Nursing | volume = 15 | issue = 1 | pages = 18–20 | year = 2006 | pmid = 16415742 | doi = 10.12968/bjon.2006.15.1.20303 }}</ref><ref name=pmid16556924>{{cite journal | vauthors = Chernoff R | title = Tube feeding patients with dementia | journal = Nutrition in Clinical Practice | volume = 21 | issue = 2 | pages = 142–146 | date = April 2006 | pmid = 16556924 | doi = 10.1177/0115426506021002142 | s2cid = 20841502 }}</ref> The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with Alzheimer's disease or their caregivers.<ref name=pracGuideAPA />

During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help of [[hospice]].<ref name=pmid12854952>{{cite journal | vauthors = Shega JW, [[Adeera Levin|Levin A]], Hougham GW, Cox-Hayley D, Luchins D, Hanrahan P, Stocking C, Sachs GA | title = Palliative Excellence in Alzheimer Care Efforts (PEACE): a program description | journal = Journal of Palliative Medicine | volume = 6 | issue = 2 | pages = 315–320 | date = April 2003 | pmid = 12854952 | doi = 10.1089/109662103764978641 | s2cid = 6072807 }}</ref>

===Diet===
Diet may be a modifiable risk factor for the development of Alzheimer's disease. The [[Mediterranean diet]], and the [[DASH diet]] are both associated with less cognitive decline. A different approach has been to incorporate elements of both of these diets into one known as the [[MIND diet]].<ref name=Acta>{{cite journal | vauthors = Dominguez LJ, Barbagallo M | title = Nutritional prevention of cognitive decline and dementia | journal = Acta Bio-Medica | volume = 89 | issue = 2 | pages = 276–290 | date = June 2018 | pmid = 29957766 | pmc = 6179018 | doi = 10.23750/abm.v89i2.7401 }}</ref> Studies of individual dietary components, minerals and supplements are conflicting as to whether they reduce AD risk or cognitive decline.<ref name=Acta /> Preliminary research indicates that abnormal eating behaviors and dietary changes are common in people with dementia, especially in later stages.<ref>{{Cite journal |last1=Cipriani |first1=Gabriele |last2=Carlesi |first2=Cecilia |last3=Lucetti |first3=Claudio |last4=Danti |first4=Sabrina |last5=Nuti |first5=Angelo |date=2016-12-01 |title=Eating Behaviors and Dietary Changes in Patients With Dementia |journal=American Journal of Alzheimer's Disease & Other Dementias |language=en |volume=31 |issue=8 |pages=706–716 |doi=10.1177/1533317516673155 |issn=1533-3175 |pmc=10852764 |pmid=27756815}}</ref>

==Prognosis==
The early stages of AD are difficult to diagnose. A definitive diagnosis is usually made once cognitive impairment compromises daily living activities, although the person may still be living independently. The symptoms will progress from mild cognitive problems, such as memory loss through increasing stages of cognitive and non-cognitive disturbances, eliminating any possibility of independent living, especially in the late stages of the disease.<ref name=pmid10653284 />

[[Life expectancy]] of people with AD is reduced.<ref name=Za2009>{{cite journal | vauthors = Zanetti O, Solerte SB, Cantoni F | title = Life expectancy in Alzheimer's disease (AD) | journal = Archives of Gerontology and Geriatrics | volume = 49 | issue = Suppl 1 | pages = 237–243 | date = 2009 | pmid = 19836639 | doi = 10.1016/j.archger.2009.09.035 }}</ref> The normal life expectancy for 60 to 70 years old is 23 to 15 years; for 90 years old it is 4.5 years.<ref>{{cite web |title=United States Life Tables, 2017 |url=https://www.cdc.gov/nchs/data/nvsr/nvsr68/nvsr68_07-508.pdf |work=National Vital Statistics Reports, CDC |access-date=10 June 2021 |archive-date=24 May 2021 |archive-url=https://web.archive.org/web/20210524202524/https://www.cdc.gov/nchs/data/nvsr/nvsr68/nvsr68_07-508.pdf |url-status=live }}</ref> Following AD diagnosis it ranges from 7 to 10 years for those in their 60s and early 70s (a loss of 13 to 8 years), to only about 3 years or less (a loss of 1.5 years) for those in their 90s.<ref name=Za2009 />

Fewer than 3% of people live more than fourteen years after diagnosis.<ref name=Molsa1995>{{cite journal | vauthors = Mölsä PK, Marttila RJ, Rinne UK | title = Long-term survival and predictors of mortality in Alzheimer's disease and multi-infarct dementia | journal = Acta Neurologica Scandinavica | volume = 91 | issue = 3 | pages = 159–164 | date = March 1995 | pmid = 7793228 | doi = 10.1111/j.1600-0404.1995.tb00426.x | s2cid = 19724937 }}</ref> Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, disturbances in the neurological examination, history of [[Falls in older adults|falls]], [[malnutrition]], [[dehydration]] and [[weight loss]].<ref name=":0" /> Other coincident diseases such as [[Cardiovascular disease|heart problems]], [[Diabetes mellitus|diabetes]], or history of [[alcohol abuse]] are also related with shortened survival.<ref name=pmid8757016>{{cite journal | vauthors = Bowen JD, Malter AD, Sheppard L, Kukull WA, McCormick WC, Teri L, Larson EB | title = Predictors of mortality in patients diagnosed with probable Alzheimer's disease | journal = Neurology | volume = 47 | issue = 2 | pages = 433–439 | date = August 1996 | pmid = 8757016 | doi = 10.1212/wnl.47.2.433 | s2cid = 24961809 }}</ref><ref name=pmid15068977>{{cite journal | vauthors = Larson EB, Shadlen MF, Wang L, McCormick WC, Bowen JD, Teri L, Kukull WA | title = Survival after initial diagnosis of Alzheimer disease | journal = Annals of Internal Medicine | volume = 140 | issue = 7 | pages = 501–509 | date = April 2004 | pmid = 15068977 | doi = 10.7326/0003-4819-140-7-200404060-00008 | s2cid = 27410149 }}</ref><ref name=pmid7792352>{{cite journal | vauthors = Jagger C, Clarke M, Stone A | title = Predictors of survival with Alzheimer's disease: a community-based study | journal = Psychological Medicine | volume = 25 | issue = 1 | pages = 171–177 | date = January 1995 | pmid = 7792352 | doi = 10.1017/S0033291700028191 | s2cid = 34066330 }}</ref> While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger.<ref name=pmid12580712>{{cite journal | vauthors = Dodge HH, Shen C, Pandav R, DeKosky ST, Ganguli M | title = Functional transitions and active life expectancy associated with Alzheimer disease | journal = Archives of Neurology | volume = 60 | issue = 2 | pages = 253–259 | date = February 2003 | pmid = 12580712 | doi = 10.1001/archneur.60.2.253 | doi-access = free | title-link = doi }}</ref> Men have a less favourable survival prognosis than women.{{update after|2023|7|10}}<ref name=Molsa1995/><ref name=Ganguli2005>{{cite journal | vauthors = Ganguli M, Dodge HH, Shen C, Pandav RS, DeKosky ST | title = Alzheimer disease and mortality: a 15-year epidemiological study | journal = Archives of Neurology | volume = 62 | issue = 5 | pages = 779–784 | date = May 2005 | pmid = 15883266 | doi = 10.1001/archneur.62.5.779 | doi-access = free | title-link = doi }}</ref>

[[Aspiration pneumonia]] is the most frequent immediate cause of death brought by AD.<ref name=":0" /> While the reasons behind the lower prevalence of [[cancer]] in AD patients remain unclear, some researchers hypothesize that biological mechanisms shared by both diseases might play a role. However, this requires further investigation.<ref>{{cite journal | vauthors = Lanni C, Masi M, Racchi M, Govoni S | title = Cancer and Alzheimer's disease inverse relationship: an age-associated diverging derailment of shared pathways | journal = Molecular Psychiatry | volume = 26 | issue = 1 | pages = 280–295 | date = January 2021 | pmid = 32382138 | doi = 10.1038/s41380-020-0760-2 }}</ref>

==Epidemiology==
{{See also|Alzheimer's disease in African Americans|Alzheimer's Disease in the East Asian Population}}

Two main measures are used in [[epidemiology|epidemiological]] studies: incidence and prevalence. [[Incidence (epidemiology)|Incidence]] is the number of new cases per unit of person-time at risk (usually number of new cases per thousand person-years); while [[prevalence]] is the total number of cases of the disease in the population at any given time.
[[File:Alzheimer's disease and other dementias world map-Deaths per million persons-WHO2012.svg|thumb|upright=1.3|Deaths per million persons in 2012 due to dementias including Alzheimer's disease
{{Div col|small=yes|colwidth=10em}}
{{legend|#ffff20|0–4}}
{{legend|#ffe820|5–8}}
{{legend|#ffd820|9–10}}
{{legend|#ffc020|11–13}}
{{legend|#ffa020|14–17}}
{{legend|#ff9a20|18–24}}
{{legend|#f08015|25–45}}
{{legend|#e06815|46–114}}
{{legend|#d85010|115–375}}
{{legend|#d02010|376–1266}}
{{div col end}}]]

Regarding incidence, [[cohort study|cohort]] [[longitudinal studies]] (studies where a disease-free population is followed over the years) provide rates between 10 and 15 per thousand person-years for all dementias and 5–8 for AD,<ref name=pmid17727890>{{cite journal | vauthors = Bermejo-Pareja F, Benito-León J, Vega S, Medrano MJ, Román GC | title = Incidence and subtypes of dementia in three elderly populations of central Spain | journal = Journal of the Neurological Sciences | volume = 264 | issue = 1–2 | pages = 63–72 | date = January 2008 | pmid = 17727890 | doi = 10.1016/j.jns.2007.07.021 | s2cid = 34341344 }}</ref><ref name=pmid12028245>{{cite journal | vauthors = Di Carlo A, Baldereschi M, Amaducci L, Lepore V, Bracco L, Maggi S, Bonaiuto S, Perissinotto E, Scarlato G, Farchi G, Inzitari D | title = Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study | journal = Journal of the American Geriatrics Society | volume = 50 | issue = 1 | pages = 41–48 | date = January 2002 | pmid = 12028245 | doi = 10.1046/j.1532-5415.2002.50006.x | s2cid = 22576935 }}</ref> which means that half of new dementia cases each year are Alzheimer's disease. Advancing age is a primary risk factor for the disease and incidence rates are not equal for all ages: every 5 years after the age of 65, the risk of acquiring the disease approximately doubles, increasing from 3 to as much as 69 per thousand person years.<ref name=pmid17727890 /><ref name=pmid12028245 /> Females with AD are more common than males, but this difference is likely due to women's longer life spans. When adjusted for age, both sexes are affected by Alzheimer's at equal rates.<ref name=Simon2018p111>{{cite book|vauthors= Simon RP, Greenberg DA, Aminoff MJ|title=Clinical neurology|date=2018|isbn=978-1-259-86173-4|edition=Tenth |publisher= McGraw Hill |location=[New York]|page=111|oclc=1012400314}}</ref> In the United States, the risk of dying from AD in 2010 was 26% higher among the non-Hispanic white population than among the non-Hispanic black population, and the Hispanic population had a 30% lower risk than the non-Hispanic white population.<ref>Tejada-Vera B. (2013). [https://purl.fdlp.gov/GPO/gpo41882 Mortality from Alzheimer's Disease in the United States: Data for 2000 and 2010.] Hyattsville, MD: [[United States Department of Health and Human Services|U.S. Department of Health and Human Services]], [[Centers for Disease Control and Prevention]], [[National Center for Health Statistics]].</ref> However, much AD research remains to be done in minority groups, such as the [[Alzheimer's disease in African Americans|African American]], [[Alzheimer's Disease in the East Asian Population|East Asian]] and [[Alzheimer's disease in the Hispanic/Latino population|Hispanic/Latino]] populations.<ref>{{cite journal | vauthors = Reitz C, Rogaeva E, Beecham GW | title = Late-onset vs nonmendelian early-onset Alzheimer disease: A distinction without a difference? | journal = Neurology. Genetics | volume = 6 | issue = 5 | pages = e512 | date = October 2020 | pmid = 33225065 | pmc = 7673282 | doi = 10.1212/NXG.0000000000000512 }}</ref><ref name="Liu-2013">{{cite journal | vauthors = Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G | title = Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy | journal = Nature Reviews. Neurology | volume = 9 | issue = 2 | pages = 106–118 | date = February 2013 | pmid = 23296339 | pmc = 3726719 | doi = 10.1038/nrneurol.2012.263 }}</ref> Studies have shown that these groups are underrepresented in clinical trials and do not have the same risk of developing AD when carrying certain genetic risk factors (i.e. APOE4), compared to their caucasian counterparts.<ref name="Liu-2013"/><ref>{{cite journal | vauthors = Massett HA, Mitchell AK, Alley L, Simoneau E, Burke P, Han SH, Gallop-Goodman G, McGowan M | title = Facilitators, Challenges, and Messaging Strategies for Hispanic/Latino Populations Participating in Alzheimer's Disease and Related Dementias Clinical Research: A Literature Review | journal = Journal of Alzheimer's Disease | volume = 82 | issue = 1 | pages = 107–127 | date = 29 June 2021 | pmid = 33998537 | doi = 10.3233/JAD-201463 | s2cid = 234745473 }}</ref><ref>{{cite journal | vauthors = Huynh RA, Mohan C | title = Alzheimer's Disease: Biomarkers in the Genome, Blood, and Cerebrospinal Fluid | journal = Frontiers in Neurology | volume = 8 | pages = 102 | date = 2017 | pmid = 28373857 | doi = 10.3389/fneur.2017.00102 | pmc = 5357660 | doi-access = free }}</ref>

The prevalence of AD in populations is dependent upon factors including incidence and survival. Since the incidence of AD increases with age, prevalence depends on the mean age of the population for which prevalence is given. In the United States in 2020, AD dementia prevalence was estimated to be 5.3% for those in the 60–74 age group, with the rate increasing to 13.8% in the 74–84 group and to 34.6% in those greater than 85.<ref>{{cite journal |vauthors=Rajan KB, Weuve J, Barnes LL, McAninch EA, Wilson RS, Evans DA |title=Population estimate of people with clinical Alzheimer's disease and mild cognitive impairment in the United States (2020-2060) |journal=Alzheimer's & Dementia |date=May 2021 |volume=17 |issue=12 |pages=1966–1975 |pmid=34043283 |doi=10.1002/alz.12362 |pmc=9013315 |s2cid=235215290 }}</ref> Prevalence rates in some less developed regions around the globe are lower.<ref>{{cite journal |vauthors=Rizzi L, Rosset I, Roriz-Cruz M |title=Global epidemiology of dementia: Alzheimer's and vascular types |journal=Biomed Res Int |volume=2014 |issue= |pages=908915 |date=2014 |pmid=25089278 |pmc=4095986 |doi=10.1155/2014/908915 |doi-access=free | title-link=doi }}</ref><ref name=pmid16360788>{{cite journal|vauthors=Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M|date=December 2005|title=Global prevalence of dementia: a Delphi consensus study|journal=Lancet|volume=366|issue=9503|pages=2112–2117|doi=10.1016/S0140-6736(05)67889-0|pmc=2850264|pmid=16360788}}</ref> Both the prevalence and incidence rates of AD are steadily increasing, however the prevalence rate is estimated to triple by 2050 reaching 152 million, compared to the 50 million people with AD globally in 2020.<ref name=Breijyeh2020/><ref>{{cite journal | vauthors = Li F, Qin W, Zhu M, Jia J | title = Model-Based Projection of Dementia Prevalence in China and Worldwide: 2020-2050 | journal = Journal of Alzheimer's Disease | volume = 82 | issue = 4 | pages = 1823–1831 | date = 1 January 2021 | pmid = 34219732 | doi = 10.3233/JAD-210493 | publisher = IOS Press | s2cid = 235735045 }}</ref><ref>{{Cite journal |last1=Nichols |first1=Emma |last2=Steinmetz |first2=Jaimie D |last3=Vollset |first3=Stein Emil |last4=Vos |first4=Theo |last5=Fukutaki |first5=Kai |last6=Chalek |first6=Julian |date=January 6, 2022 |title=Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019 |journal=The Lancet Public Health |volume=7 |issue=2 |pages=e105–e125 |doi=10.1016/S2468-2667(21)00249-8 |issn=2468-2667 |pmid=34998485 |pmc=8810394 |hdl=2440/135555 }}</ref>

==History==
[[File:Auguste D aus Marktbreit.jpg|thumb|upright|Alois Alzheimer's patient [[Auguste Deter]] in 1902. Hers was the first described case of what became known as Alzheimer's disease.]]
The [[Classical antiquity|ancient Greek and Roman]] philosophers and [[physician]]s associated old age with increasing [[dementia]].<ref name=pmid9661992 /> It was not until 1901 that German psychiatrist [[Alois Alzheimer]] identified the first case of what became known as Alzheimer's disease, named after him, in a fifty-year-old woman he called [[Auguste D]]. He followed her case until she died in 1906 when he first reported publicly on it.<ref>Auguste D.:
* {{cite journal | vauthors = Alzheimer A |title=Über eine eigenartige Erkrankung der Hirnrinde|trans-title=About a peculiar disease of the cerebral cortex |journal=Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtlich Medizin|volume=64|issue=1–2|pages=146–148|year=1907|language=de}}
* {{cite journal | vauthors = | title = About a peculiar disease of the cerebral cortex. By Alois Alzheimer, 1907 (Translated by L. Jarvik and H. Greenson) | journal = Alzheimer Disease and Associated Disorders | volume = 1 | issue = 1 | pages = 3–8 | year = 1987 | pmid = 3331112 | translator = H. Greenson }}
* {{cite book | vauthors = Maurer U, Maurer K |title=Alzheimer: The Life of a Physician and the Career of a Disease |publisher=Columbia University Press |location=New York|year=2003|page=[https://archive.org/details/alzheimerlifeofp00maur/page/270 270]|isbn=978-0-231-11896-5 |url=https://archive.org/details/alzheimerlifeofp00maur/page/270}}</ref> During the next five years, eleven similar cases were reported in the [[medical literature]], some of them already using the term Alzheimer's disease.<ref name=pmid9661992>{{cite journal | vauthors = Berchtold NC, Cotman CW | title = Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s | journal = Neurobiology of Aging | volume = 19 | issue = 3 | pages = 173–189 | year = 1998 | pmid = 9661992 | doi = 10.1016/S0197-4580(98)00052-9 | s2cid = 24808582 }}</ref> The disease was first described as a distinctive disease by [[Emil Kraepelin]] after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D.<ref>{{cite journal |vauthors=Berrios GE |title=Alzheimer's Disease: A Conceptual History |journal=Int. J. Geriatr. Psychiatry |volume=5|issue=6|pages=355–365|year=1990|doi=10.1002/gps.930050603|s2cid=145155424}}</ref> He included ''Alzheimer's disease'', also named ''presenile'' [[dementia]] by Kraepelin, as a subtype of ''senile dementia'' in the eighth edition of his ''Textbook of Psychiatry'', published on 15 July 1910.<ref name=isbn1-4325-0833-4>{{cite book | vauthors = Kraepelin E |translator=Diefendorf AR |title=Clinical Psychiatry: A Textbook For Students And Physicians (Reprint) |publisher=Kessinger Publishing|year=2007|page=568|isbn=978-1-4325-0833-3}}</ref>

For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference on Alzheimer's disease concluded that the clinical and [[pathological]] manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility that they had different causes.<ref name=isbn0-89004-225-X>{{cite book |veditors=Katzman R, Terry RD, Bick KL |title=Alzheimer's Disease: Senile Dementia and Related Disorders |publisher=Raven Press|location=New York|year=1978|page=595|isbn=978-0-89004-225-0}}</ref> This eventually led to the diagnosis of ''Alzheimer's disease'' independent of age.<ref name=pmid9702682>{{cite journal | vauthors = Boller F, Forbes MM | title = History of dementia and dementia in history: an overview | journal = Journal of the Neurological Sciences | volume = 158 | issue = 2 | pages = 125–133 | date = June 1998 | pmid = 9702682 | doi = 10.1016/S0022-510X(98)00128-2 | s2cid = 42399340 }}</ref> The term ''senile dementia of the Alzheimer type'' (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used to describe those who were younger. Eventually, the term Alzheimer's disease was formally adopted in medical [[nomenclature]] to describe individuals of all ages with a characteristic common symptom pattern, disease course, and [[neuropathology]].<ref name=pmid3531918>{{cite journal | vauthors = Amaducci LA, Rocca WA, Schoenberg BS | title = Origin of the distinction between Alzheimer's disease and senile dementia: how history can clarify nosology | journal = Neurology | volume = 36 | issue = 11 | pages = 1497–1499 | date = November 1986 | pmid = 3531918 | doi = 10.1212/wnl.36.11.1497 | s2cid = 7689479 }}</ref>

The [[National Institute of Neurological and Communicative Disorders and Stroke]] (NINCDS) and the [[Alzheimer's Disease and Related Disorders Association]] (ADRDA, now known as the [[Alzheimer's Association]]) established the most commonly used [[NINCDS-ADRDA Alzheimer's Criteria]] for diagnosis in 1984,<ref name=pmid6610841>{{cite journal|vauthors=McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM|date=July 1984|title=Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease|journal=Neurology|volume=34|issue=7|pages=939–944|doi=10.1212/wnl.34.7.939|pmid=6610841|doi-access=free | title-link=doi|s2cid=11646075}}</ref> extensively updated in 2007.<ref name=pmid17616482>{{cite journal | vauthors = Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P | title = Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria | journal = The Lancet. Neurology | volume = 6 | issue = 8 | pages = 734–746 | date = August 2007 | pmid = 17616482 | doi = 10.1016/S1474-4422(07)70178-3 | s2cid = 7356809 }}</ref><ref name=Stern2020 /> These criteria require that the presence of [[Developmental disability|cognitive impairment]], and a suspected dementia syndrome, be confirmed by [[Neuropsychological assessment|neuropsychological testing]] for a clinical diagnosis of possible or probable Alzheimer's disease. A [[histopathologic]] confirmation including a [[microscopic]] examination of [[brain tissue]] is required for a definitive diagnosis. Good [[Reliability (statistics)|statistical reliability]] and [[Validity (statistics)|validity]] have been shown between the diagnostic criteria and definitive histopathological confirmation.<ref name=pmid7986174>{{cite journal | vauthors = Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF | title = Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative | journal = Archives of Neurology | volume = 51 | issue = 12 | pages = 1198–1204 | date = December 1994 | pmid = 7986174 | doi = 10.1001/archneur.1994.00540240042014 }}</ref>

==Society and culture==
{{See also|Alzheimer's disease organizations}}

===Social costs===
Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for societies worldwide.<ref name=El-Hayek2019>{{cite journal |vauthors = El-Hayek YH, Wiley RE, Khoury CP, Daya RP, Ballard C, Evans AR, Karran M, Molinuevo JL, Norton M, Atri A |title=Tip of the Iceberg: Assessing the Global Socioeconomic Costs of Alzheimer's Disease and Related Dementias and Strategic Implications for Stakeholders |journal=Journal of Alzheimer's Disease |volume=70 |issue=2 |pages=323–341 |date=2019 |pmid=31256142 |pmc=6700654 |doi=10.3233/JAD-190426 }}</ref> As populations age, these costs will probably increase and become an important [[social issue|social problem]] and economic burden.<ref name=Wong2020>{{cite journal |vauthors=Wong W |title=Economic burden of Alzheimer disease and managed care considerations |journal=Am J Manag Care |volume=26 |issue=8 Suppl |pages=S177–S183 |date=August 2020 |pmid=32840331 |doi=10.37765/ajmc.2020.88482 |s2cid=221308149 |url=https://www.ajmc.com/view/economic-burden-of-alzheimer-disease-and-managed-care-considerations |doi-access=free |access-date=17 March 2022 |archive-date=25 February 2022 |archive-url=https://web.archive.org/web/20220225012224/https://www.ajmc.com/view/economic-burden-of-alzheimer-disease-and-managed-care-considerations |url-status=live }}</ref> Costs associated with AD include direct and indirect medical costs, which vary between countries depending on social care for a person with AD.<ref name=El-Hayek2019 /><ref name=Tahami2022>{{cite journal |vauthors=Tahami Monfared AA, Byrnes MJ, White LA, Zhang Q |title=The Humanistic and Economic Burden of Alzheimer's Disease |journal=Neurol Ther |date=February 2022 |volume=11 |issue=2 |pages=525–551 |pmid=35192176 |doi=10.1007/s40120-022-00335-x |pmc=9095804 |s2cid=247014076 }}</ref><ref name=Kosaner2021>{{cite journal |vauthors=Kosaner Kließ M, Martins R, Connolly MP |title=Major Cost Drivers in Assessing the Economic Burden of Alzheimer's Disease: A Structured, Rapid Review |journal=J Prev Alzheimers Dis |volume=8 |issue=3 |pages=362–370 |date=2021 |pmid=34101795 |doi=10.14283/jpad.2021.17 |s2cid=233403683 |doi-access=free }}</ref> Direct costs include doctor visits, hospital care, medical treatments, [[nursing home care]], specialized equipment, and household expenses.<ref name=El-Hayek2019 /><ref name=Wong2020 /> Indirect costs include the cost of informal care and the loss in [[productivity]] of informal caregivers.<ref name=Wong2020 />

In the United States {{as of|2019|lc=y}}, informal (family) care is estimated to constitute nearly three-fourths of caregiving for people with AD at a cost of US$234 billion per year and approximately 18.5 billion hours of care.<ref name=El-Hayek2019 /> The cost to society worldwide to care for individuals with AD is projected to increase nearly ten-fold, and reach about US$9.1 trillion by 2050.<ref name=Tahami2022 />

Costs for those with more severe dementia or behavioral disturbances are higher and are related to the additional caregiving time to provide physical care.<ref name=Kosaner2021 />

===Caregiving burden===
{{Further|Caregiving and dementia}}
{{update section|date=February 2022}}
Individuals with Alzheimer's will require assistance in their lifetime, and care will most likely come in the form of a full-time [[caregiver]] which is often a role that is taken on by the spouse or a close relative. Caregiving tends to include physical and emotional burdens as well as time and financial strain at times on the person administering the aid.<ref>{{cite journal | vauthors = Demirbas M, Hahn-Pedersen JH, Jørgensen HL | title = Comparison Between Burden of Care Partners of Individuals with Alzheimer's Disease Versus Individuals with Other Chronic Diseases | journal = Neurology and Therapy | volume = 12 | issue = 4 | pages = 1051–1068 | date = August 2023 | pmid = 37222859 | pmc = 10310688 | doi = 10.1007/s40120-023-00493-6 }}</ref><ref name=metlife.com>{{cite web |title=The MetLife study of Alzheimer's disease: The caregiving experience |date=August 2006|publisher=MetLife Mature Market Institute|access-date=5 February 2011 |url=http://www.metlife.com/assets/cao/mmi/publications/studies/mmi-alzheimers-disease-caregiving-experience-study.pdf |archive-url=https://web.archive.org/web/20110108073750/http://www.metlife.com/assets/cao/mmi/publications/studies/mmi-alzheimers-disease-caregiving-experience-study.pdf|archive-date=8 January 2011|url-status=dead}}</ref> Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical, or economic aspects.<ref name=Thom2007 /><ref name=pmid10489656>{{cite journal | vauthors = Schneider J, Murray J, Banerjee S, Mann A | title = EUROCARE: a cross-national study of co-resident spouse carers for people with Alzheimer's disease: I—Factors associated with carer burden | journal = International Journal of Geriatric Psychiatry | volume = 14 | issue = 8 | pages = 651–661 | date = August 1999 | pmid = 10489656 | doi = 10.1002/(SICI)1099-1166(199908)14:8<651::AID-GPS992>3.0.CO;2-B | s2cid = 27346798 | doi-access = free }}</ref><ref name=pmid10489657>{{cite journal | vauthors = Murray J, Schneider J, Banerjee S, Mann A | title = EUROCARE: a cross-national study of co-resident spouse carers for people with Alzheimer's disease: II—A qualitative analysis of the experience of caregiving | journal = International Journal of Geriatric Psychiatry | volume = 14 | issue = 8 | pages = 662–667 | date = August 1999 | pmid = 10489657 | doi = 10.1002/(SICI)1099-1166(199908)14:8<662::AID-GPS993>3.0.CO;2-4 | s2cid = 41741923 }}</ref> Home care is usually preferred by both those people with Alzheimer's disease as well as their families.<ref name=pmid18044111>{{cite journal | vauthors = Zhu CW, Sano M | title = Economic considerations in the management of Alzheimer's disease | journal = Clinical Interventions in Aging | volume = 1 | issue = 2 | pages = 143–154 | year = 2006 | pmid = 18044111 | pmc = 2695165 | doi = 10.2147/ciia.2006.1.2.143 | doi-access = free }}</ref> This option also delays or eliminates the need for more professional and costly levels of care.<ref name=pmid18044111 /><ref>{{cite journal | vauthors = Gaugler JE, Kane RL, Kane RA, Newcomer R | title = Early community-based service utilization and its effects on institutionalization in dementia caregiving | journal = The Gerontologist | volume = 45 | issue = 2 | pages = 177–185 | date = April 2005 | pmid = 15799982 | doi = 10.1093/geront/45.2.177 | doi-access = free | title-link = doi }}</ref> Nevertheless, two-thirds of nursing home residents have dementias.<ref name=pracGuideAPA />

[[Depression of Alzheimer disease|Dementia]] caregivers are subject to high rates of physical and [[mental disorder|mental]] disorders.<ref name=pmid12480441>{{cite journal | vauthors = Ritchie K, Lovestone S | title = The dementias | journal = Lancet | volume = 360 | issue = 9347 | pages = 1759–1766 | date = November 2002 | pmid = 12480441 | doi = 10.1016/S0140-6736(02)11667-9 | s2cid = 21404062 }}</ref> Factors associated with greater psychosocial problems of the primary caregivers include having an affected person at home, the caregiver being a spouse, demanding behaviors of the cared person such as depression, behavioral disturbances, hallucinations, sleep problems or walking disruptions and [[social isolation]].<ref name=pmid2241719>{{cite journal | vauthors = Brodaty H, Hadzi-Pavlovic D | title = Psychosocial effects on carers of living with persons with dementia | journal = The Australian and New Zealand Journal of Psychiatry | volume = 24 | issue = 3 | pages = 351–361 | date = September 1990 | pmid = 2241719 | doi = 10.3109/00048679009077702 | s2cid = 11788466 }}</ref><ref name=pmid9646153>{{cite journal | vauthors = Donaldson C, Tarrier N, Burns A | title = Determinants of carer stress in Alzheimer's disease | journal = International Journal of Geriatric Psychiatry | volume = 13 | issue = 4 | pages = 248–256 | date = April 1998 | pmid = 9646153 | doi = 10.1002/(SICI)1099-1166(199804)13:4<248::AID-GPS770>3.0.CO;2-0 | s2cid = 22187694 }}</ref> In the United States, the yearly cost of caring for a person with dementia ranges from $41,689-$56,290 per year.<ref name="Hurd 2013">{{cite journal |last1=Hurd |first1=Michael D. |last2=Martorell |first2=Paco |last3=Delavande |first3=Adeline |last4=Mullen |first4=Kathleen J. |last5=Langa |first5=Kenneth M. |title=Monetary Costs of Dementia in the United States |journal=New England Journal of Medicine |date=4 April 2013 |volume=368 |issue=14 |pages=1326–1334 |doi=10.1056/NEJMsa1204629|pmid=23550670 |pmc=3959992 }}</ref> Other estimates range from $28,078-$56,022 per year for formal medical care and $36,667-$92,689 for informal care provided by a relative or friend (assuming market value replacement costs for the care provided by the informal caregiver) and $15,792-$71,813 in lost wages.<ref name="Nandi 2024">{{cite journal |last1=Nandi |first1=Arindam |last2=Counts |first2=Nathaniel |last3=Bröker |first3=Janina |last4=Malik |first4=Sabrina |last5=Chen |first5=Simiao |last6=Han |first6=Rachael |last7=Klusty |first7=Jessica |last8=Seligman |first8=Benjamin |last9=Tortorice |first9=Daniel |last10=Vigo |first10=Daniel |last11=Bloom |first11=David E. |title=Cost of care for Alzheimer's disease and related dementias in the United States: 2016 to 2060 |journal=npj Aging |date=8 February 2024 |volume=10 |issue=1 |page=13 |doi=10.1038/s41514-024-00136-6|pmid=38331952 |pmc=10853249 }}</ref>

[[Cognitive behavioral therapy]] and the teaching of [[Coping (psychology)|coping strategies]] either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.<ref name=Thom2007 /><ref name=pmid11511058>{{cite journal | vauthors = Pusey H, Richards D | title = A systematic review of the effectiveness of psychosocial interventions for carers of people with dementia | journal = Aging & Mental Health | volume = 5 | issue = 2 | pages = 107–119 | date = May 2001 | pmid = 11511058 | doi = 10.1080/13607860120038302 | s2cid = 32517015 }}</ref>

===Media===
{{Main|Alzheimer's disease in the media}}

Alzheimer's disease has been portrayed in films such as: ''[[Iris (2001 film)|Iris]]'' (2001), based on [[John Bayley (writer)|John Bayley]]'s memoir of his wife [[Iris Murdoch]];<ref>{{cite book |title=Iris: A Memoir of Iris Murdoch | vauthors = Bayley J |publisher=Abacus|location=London|year=2000|isbn=978-0-349-11215-2|oclc=41960006}}</ref> ''[[The Notebook (2004 film)|The Notebook]]'' (2004), based on [[Nicholas Sparks]]'s 1996 [[The Notebook (novel)|novel of the same name]];<ref>{{cite book |title=The notebook| vauthors = Sparks N |year=1996 |publisher=Thorndike Press |location=Thorndike, Maine|page=[https://archive.org/details/notebook00spar_1/page/268 268]|isbn=978-0-7862-0821-0 |url=https://archive.org/details/notebook00spar_1/page/268}}</ref> ''[[A Moment to Remember]]'' (2004); ''[[Thanmathra]]'' (2005);<ref>{{cite web |url=http://www.webindia123.com/movie/regional/thanmatra/index.htm |title=Thanmathra |publisher=Webindia123.com |access-date=24 January 2008 |archive-url=https://web.archive.org/web/20071106105455/http://www.webindia123.com/movie/regional/thanmatra/index.htm|archive-date=6 November 2007}}</ref> ''[[Memories of Tomorrow (Ashita no Kioku)]]'' (2006), based on Hiroshi Ogiwara's novel of the same name;<ref>{{cite book | vauthors = Ogiwara H |year=2004 |title=Ashita no Kioku |location=Tōkyō|publisher=Kōbunsha|isbn=978-4-334-92446-1|oclc=57352130|language=ja}}</ref> ''[[Away from Her]]'' (2006), based on [[Alice Munro]]'s [[short story]] ''[[Hateship, Friendship, Courtship, Loveship, Marriage|The Bear Came over the Mountain]]'';<ref>{{cite book|title=Hateship, Friendship, Courtship, Loveship, Marriage: Stories | vauthors = Munro A |location=New York|publisher=A.A. Knopf|year=2001|isbn=978-0-375-41300-1|oclc=46929223|title-link=Hateship, Friendship, Courtship, Loveship, Marriage}}</ref> ''[[Still Alice]]'' (2014), about a [[Columbia University]] professor who has early onset Alzheimer's disease, based on [[Lisa Genova]]'s [[Still Alice (novel)|2007 novel of the same name]] and featuring [[Julianne Moore]] in the title role. Documentaries on Alzheimer's disease include ''Malcolm and Barbara: A Love Story'' (1999) and ''Malcolm and Barbara: Love's Farewell'' (2007), both featuring [[Malcolm Pointon]].<ref>{{cite web |url=http://www.dfgdocs.com/Directory/Titles/700.aspx |title=Malcolm and Barbara: A love story |publisher=Dfgdocs|access-date=24 January 2008|url-status=dead |archive-url=https://web.archive.org/web/20080524213821/http://www.dfgdocs.com/Directory/Titles/700.aspx|archive-date=24 May 2008}}</ref><ref>{{cite web |url=https://www.bbc.co.uk/cambridgeshire/content/articles/2007/08/06/pointon_audio_feature.shtml |title=Malcolm and Barbara: A love story |publisher=BBC Cambridgeshire|access-date=2 March 2008 |archive-url=https://web.archive.org/web/20121110084233/http://www.bbc.co.uk/cambridgeshire/content/articles/2007/08/06/pointon_audio_feature.shtml|archive-date=10 November 2012}}</ref><ref>{{cite news |url=https://www.theguardian.com/media/2007/aug/07/broadcasting.itv |title=Alzheimer's film-maker to face ITV lawyers |publisher=Guardian Media|date=7 August 2007|access-date=24 January 2008|location=London|vauthors=Plunkett J |archive-url=https://web.archive.org/web/20080115132419/http://www.guardian.co.uk/media/2007/aug/07/broadcasting.itv|archive-date=15 January 2008}}</ref>

Alzheimer's disease has also been portrayed in music by English musician [[The Caretaker (musician)|the Caretaker]] in releases such as ''[[Persistent Repetition of Phrases]]'' (2008), ''[[An Empty Bliss Beyond This World]]'' (2011), and ''[[Everywhere at the End of Time]]'' (2016{{endash}}2019).<ref>{{cite web |url=https://www.factmag.com/2009/08/26/the-caretaker-persistent-repetition-of-phrases/ |title=The Caretaker: ''Persistent Repetition of Phrases'' |date=26 August 2009|access-date=9 April 2021|website=[[Fact (UK magazine)|Fact]] |archive-url=https://web.archive.org/web/20210415031615/https://www.factmag.com/2009/08/26/the-caretaker-persistent-repetition-of-phrases/|archive-date=15 April 2021|url-status=live}}</ref><ref>{{cite web |url=https://pitchfork.com/reviews/albums/15518-an-empty-bliss-beyond-this-world/ |title=The Caretaker: ''An Empty Bliss Beyond This World'' Album Review |date=14 June 2011|access-date=19 February 2021|website=[[Pitchfork (website)|Pitchfork]]| vauthors = Powell M |archive-url=https://web.archive.org/web/20110618005627/http://www.pitchfork.com/reviews/albums/15518-an-empty-bliss-beyond-this-world|archive-date=18 June 2011|url-status=live}}</ref><ref>{{cite web |url=https://www.nytimes.com/2020/10/23/style/tiktok-caretaker-challenge-dementia.html |title=Why Are TikTok Teens Listening to an Album About Dementia? |date=23 October 2020|access-date=21 April 2021 |website=The New York Times| vauthors = Ezra M |archive-url=https://web.archive.org/web/20201023171008/https://www.nytimes.com/2020/10/23/style/tiktok-caretaker-challenge-dementia.html|archive-date=23 October 2020|url-status=live|url-access=limited}}</ref> Paintings depicting the disorder include the late works by American artist [[William Utermohlen]], who drew self-portraits from 1995 to 2000 as an experiment of showing his disease through art.<ref>{{cite web |url=https://www.theguardian.com/culture/2015/jul/19/dementia-and-the-arts-fiction-films-drama-poetry-painting |title=Words fail us: dementia and the arts |date=19 July 2015|access-date=14 June 2021 |website=[[The Guardian]]| vauthors = Gerrard N |archive-url=https://web.archive.org/web/20150719073843/https://www.theguardian.com/culture/2015/jul/19/dementia-and-the-arts-fiction-films-drama-poetry-painting |archive-date=19 July 2015|url-status=live}}</ref><ref>{{cite news |url=https://www.nytimes.com/2006/10/24/health/24alzh.html |title=Self-Portraits Chronicle a Descent Into Alzheimer's |date=24 October 2006|access-date=14 June 2021 |website=The New York Times | vauthors = Grady D |archive-url=https://web.archive.org/web/20061024065357/https://www.nytimes.com/2006/10/24/health/24alzh.html|archive-date=24 October 2006|url-status=live|url-access=limited}}</ref>

==Research directions==
{{see also|Anti-amyloid drugs}}
Antibodies may have the ability to alter the disease course by targeting amyloid beta with immunotherapy medications such as [[donanemab]], [[aducanumab]], and [[lecanemab]].<ref>{{cite journal | vauthors = Shi M, Chu F, Zhu F, Zhu J | title = Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer's Disease: A Focus on Aducanumab and Lecanemab | journal = Frontiers in Aging Neuroscience | volume = 14 | issue =  | pages = 870517 | date = 2022 | pmid = 35493943 | pmc = 9039457 | doi = 10.3389/fnagi.2022.870517 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F | title = Alzheimer's disease drug development pipeline: 2023 | journal = Alzheimer's & Dementia | volume = 9 | issue = 2 | pages = e12385 | date = 2023 | pmid = 37251912 | pmc = 10210334 | doi = 10.1002/trc2.12385 }}</ref><ref>{{cite web |url= https://www.nia.nih.gov/health/how-alzheimers-disease-treated |title= How Is Alzheimer's Disease Treated? |publisher= U.S. [[National Institute on Aging]] |date= 1 April 2023 |access-date= 10 July 2023}}</ref> Aducanumab was approved by the US [[Food and Drug Administration]] (FDA) in 2021, using the [[Accelerated approval (FDA)|accelerated approval process]], although the approval generated controversy and more evidence is needed to address administration, safety, and effectiveness.<ref name=Vaz2022>{{cite journal | vauthors = Vaz M, Silva V, Monteiro C, Silvestre S | title = Role of Aducanumab in the Treatment of Alzheimer's Disease: Challenges and Opportunities | journal = Clinical Interventions in Aging | volume = 17 | issue =  | pages = 797–810 | date = 2022 | pmid = 35611326 | pmc = 9124475 | doi = 10.2147/CIA.S325026 | doi-access = free }}</ref><ref name=Day2022>{{cite journal | vauthors = Day GS, Scarmeas N, Dubinsky R, Coerver K, Mostacero A, West B, Wessels SR, Armstrong MJ | title = Aducanumab Use in Symptomatic Alzheimer Disease Evidence in Focus: A Report of the AAN Guidelines Subcommittee | journal = Neurology | volume = 98 | issue = 15 | pages = 619–631 | date = April 2022 | pmid = 35197360 | pmc = 9012273 | doi = 10.1212/wnl.0000000000200176 }}</ref><ref name=Mahase2021>{{cite journal | vauthors = Mahase E | title = Three FDA advisory panel members resign over approval of Alzheimer's drug | journal = BMJ | volume = 373 | issue =  | pages = n1503 | date = June 2021 | pmid = 34117086 | doi = 10.1136/bmj.n1503 | url = https://www.bmj.com/content/373/bmj.n1503.long | access-date = 7 July 2023 | url-status = live | s2cid = 235405355 | archive-url = https://web.archive.org/web/20230708042005/https://www.bmj.com/content/373/bmj.n1503.long | archive-date = 8 July 2023 }}</ref><ref name=NYT2021>{{cite news |url= https://www.nytimes.com/2021/06/10/health/aduhelm-fda-resign-alzheimers.html |title= Three F.D.A. Advisers Resign Over Agency's Approval of Alzheimer's Drug |work= The New York Times |vauthors= Belluck P, Robbins R |date= June 10, 2021 |access-date= July 7, 2023 |archive-date= 14 November 2021 |archive-url= https://web.archive.org/web/20211114103425/https://www.nytimes.com/2021/06/10/health/aduhelm-fda-resign-alzheimers.html |url-status= live }}</ref> It has less effectiveness in people who already had severe Alzheimer's symptoms.<ref>{{cite journal | vauthors = Abyadeh M, Gupta V, Gupta V, Chitranshi N, Wu Y, Amirkhani A, Meyfour A, Sheriff S, Shen T, Dhiman K, Ghasem HS, Paul AH, Stuart LG, Mirzaei M | title = Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer's Disease | journal = Aging and Disease | volume = 12 | issue = 8 | pages = 1964–1976 | date = December 2021 | pmid = 34881080 | pmc = 8612603 | doi = 10.14336/AD.2021.0719 }}</ref> In early 2024, Biogen announced it would discontinue aducanumab.<ref name=":1">{{Cite news |last=Wade |first=Grace |date=August 3, 2024 |title=The truth about Alzheimer's drugs |work=New Scientist |page=14}}</ref>

Lecanemab, which clears plaques and reduces amyloid proteins,<ref name=":2">{{Cite news |last=Wade |first=Grace |date=August 3, 2024 |title=The truth about Alzheimer's drugs |work=New Scientist |page=15}}</ref> was approved via the FDA accelerated approval process,<ref>{{cite journal | vauthors = Marsool MD, Prajjwal P, Reddy YB, Marsool AD, Lam JR, Nandwana V | title = Newer modalities in the management of Alzheimer's dementia along with the role of aducanumab and lecanemab in the treatment of its refractory cases | journal = Disease-a-Month | volume = 69 | issue = 5 | pages = 101547 | date = May 2023 | pmid = 36931947 | doi = 10.1016/j.disamonth.2023.101547 | s2cid = 257568052 }}</ref><ref name="FDA PR 20230106">{{cite press release | title=FDA Grants Accelerated Approval for Alzheimer's Disease Treatment | publisher=U.S. [[Food and Drug Administration]] (FDA) | date=6 January 2023 | url=https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment | access-date=7 January 2023 | archive-date=7 January 2023 | archive-url=https://web.archive.org/web/20230107000220/https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment | url-status=live }} {{PD-notice}}</ref><ref>{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2023/761269Orig1s000SumR.pdf |title=Lecanemab Summary Review | publisher = U.S. [[Food and Drug Administration]] (FDA) |access-date=7 January 2023 |archive-date=7 January 2023 |archive-url=https://web.archive.org/web/20230107005316/https://www.accessdata.fda.gov/drugsatfda_docs/summary_review/2023/761269Orig1s000SumR.pdf |url-status=live }}</ref> and was converted to traditional approval in July 2023, after further testing, along with the addition of a [[boxed warning]] about [[amyloid-related imaging abnormalities]].<ref name="FDA PR 20230706">{{cite press release |title=FDA Converts Novel Alzheimer's Disease Treatment to Traditional Approval |website=U.S. [[Food and Drug Administration]] (FDA) |date=6 July 2023 |url=https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval |access-date=6 July 2023}} {{PD-notice}}</ref><ref name="NYT20230706">{{cite news | title=FDA Makes Alzheimer's Drug Leqembi Widely Accessible | website=[[The New York Times]] | date=6 July 2023 | url=https://www.nytimes.com/2023/07/06/health/alzheimers-leqembi-medicare.html | access-date=8 July 2023 | archive-date=7 July 2023 | archive-url=https://web.archive.org/web/20230707193529/https://www.nytimes.com/2023/07/06/health/alzheimers-leqembi-medicare.html | url-status=live }}</ref> As of early August 2024, lecanemab was approved for sale in Japan, South Korea, China, Hong Kong and Israel although it was recommended against approval by an advisory body of the European Union on July 26, citing its side effects.<ref name=":1" />

[[Donanemab]], which clears plaques,<ref name=":2" /> was approved by the FDA in July 2024.<ref name="FDA PR 20240702">{{cite press release | title=FDA approves treatment for adults with Alzheimer's disease | website=U.S. [[Food and Drug Administration]] (FDA) | date=2 July 2024 | url=https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-adults-alzheimers-disease | access-date=2 July 2024 | archive-date=2 July 2024 | archive-url=https://web.archive.org/web/20240702222134/https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-adults-alzheimers-disease | url-status=live }}</ref> Anti-amyloid drugs also cause brain shrinkage.<ref>{{cite journal | vauthors = Alves F, Kalinowski P, Ayton S | title = Accelerated Brain Volume Loss Caused by Anti-β-Amyloid Drugs: A Systematic Review and Meta-analysis | journal = Neurology | volume = 100 | issue = 20 | pages = e2114–e2124 | date = May 2023 | pmid = 36973044 | pmc = 10186239 | doi = 10.1212/WNL.0000000000207156 }}</ref> The cholinesterase inhibitor [[benzgalantamine]] was approved by the FDA in July 2024.<ref>{{cite press release | title=Alpha Cognition's Oral Therapy Zunveyl Receives FDA Approval to Treat Alzheimer's Disease | publisher=Alpha Cognition | via=Business Wire | date=29 July 2024 | url=https://www.businesswire.com/news/home/20240729327804/en/ | access-date=4 August 2024}}</ref>

Specific medications that may reduce the risk or progression of Alzheimer's disease have been studied.<ref name=McDade2021 /> The research trials investigating medications generally impact [[Aβ]] [[amyloid plaques|plaques]], inflammation, [[Apolipoprotein E|APOE]], neurotransmitter receptors, neurogenesis, [[growth factor]]s or hormones.<ref name=McDade2021>{{cite journal |vauthors=McDade E, Llibre-Guerra JJ, Holtzman DM, Morris JC, Bateman RJ |title=The informed road map to prevention of Alzheimer Disease: A call to arms |journal=Mol Neurodegener |volume=16 |issue=1 |pages=49 |date=July 2021 |pmid=34289882 |pmc=8293489 |doi=10.1186/s13024-021-00467-y |doi-access=free }}</ref><ref name=Lemche2018>{{cite journal |vauthors=Lemche E |title=Early Life Stress and Epigenetics in Late-onset Alzheimer's Dementia: A Systematic Review |journal=Curr Genomics |volume=19 |issue=7 |pages=522–602 |date=November 2018 |pmid=30386171 |pmc=6194433 |doi=10.2174/1389202919666171229145156}}</ref><ref>{{cite journal |vauthors=Galle SA, Geraedts IK, Deijen JB, Milders MV, Drent ML |title=The Interrelationship between Insulin-Like Growth Factor 1, Apolipoprotein E ε4, Lifestyle Factors, and the Aging Body and Brain |journal=J Prev Alzheimers Dis |volume=7 |issue=4 |pages=265–273 |date=2020 |pmid=32920629 |doi=10.14283/jpad.2020.11 |s2cid=214784366 |doi-access=free | title-link=doi }}</ref>

[[Machine learning]] algorithms with [[electronic health record]]s are being studied as a way to predict Alzheimer's disease earlier.<ref>{{cite journal |vauthors = Li Q, Yang X, Xu J, Guo Y, He X, Hu H, Lyu T, Marra D, Miller A, Smith G, DeKosky S, Boyce RD, Schliep K, Shenkman E, Maraganore D, Wu Y, Bian J |date=February 2023 |title=Early prediction of Alzheimer's disease and related dementias using real-world electronic health records |journal=Alzheimer's & Dementia |volume= 19|issue= 8|pages=3506–3518 |doi=10.1002/alz.12967 |pmid=36815661 |s2cid=257101613 |doi-access=free |pmc=10976442 }}</ref>

=== Focused ultrasound for medication delivery ===
In 2024, a new technique of using [[focused ultrasound]] for the delivery of medication past the [[blood-brain barrier]] (BBB) is being tested. At the point where the ultrasound beams converge, the focused ultrasound produces several therapeutic effects without incisions or radiation. This can cause opening of the blood-brain barrier (BBB), which may aid in the removal of beta amyloid or tao from the brain.<ref name="Scott 2024">{{cite journal |last1=Scott |first1=Kurt |last2=Klaus |first2=Stephen P. |title=Focused ultrasound therapy for Alzheimer's disease: exploring the potential for targeted amyloid disaggregation |journal=Frontiers in Neurology |date=6 August 2024 |volume=15 |doi=10.3389/fneur.2024.1426075|doi-access=free |pmid=39165269 |pmc=11333319 }}</ref>

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Van Acker ZP, Perdok A, Bretou M, Annaert W | title = The microglial lysosomal system in Alzheimer's disease: Guardian against proteinopathy | journal = Ageing Research Reviews | volume = 71 | issue = | pages = 101444 | date = November 2021 | pmid = 34391945 | doi = 10.1016/j.arr.2021.101444 | s2cid = 236994329 | url = https://lirias.kuleuven.be/handle/123456789/685536 }}
* {{cite journal | vauthors = Xi Y, Chen Y, Jin Y, Han G, Song M, Song T, Shi Y, Tao L, Huang Z, Zhou J, Ding Y, Zhang H | title = Versatile nanomaterials for Alzheimer's disease: Pathogenesis inspired disease-modifying therapy | journal = Journal of Controlled Release | volume = 345 | issue = | pages = 38–61 | date = May 2022 | pmid = 35257810 | doi = 10.1016/j.jconrel.2022.02.034 | s2cid = 247285338 }}

* {{cite journal | vauthors = Prasanalakshmi B, Mousmi A, Syeda M, Anandhavalli M, Linda E | title = Hybridized Deep Learning Approach for Detecting Alzheimer's Disease | journal = Biomedicines | volume = 11 | issue = 4| date = January 2023 | pages = 4–8 | pmid = 9855764 | doi = 10.3390/biomedicines11010149 | doi-access = free | s2cid = 255745038| pmc = 9855764 }}
{{refend}}

== External links ==
{{Commons category|Alzheimer's disease}}
{{Wiktionary|Alzheimer's disease}}
* {{cite web |title=Alzheimer's Disease Research Timeline – Alzforum |url=http://www.alzforum.org/timeline/alzheimers-disease|website=www.alzforum.org}}
* {{cite web |title=Alzheimer's Disease Brain Cell Atlas- brain-map.org |url=https://portal.brain-map.org/explore/seattle-alzheimers-disease |website=portal.brain-map.org}}
{{Medical condition classification and resources
 |DiseasesDB=490
 |ICD11={{ICD11|8A20}}
 |ICD10={{ICD10|G30}}, {{ICD10|F00}}
 |ICD9={{ICD9|331.0}}, {{ICD9|290.1}}
 |ICDO=
 |Curlie= Health/Conditions_and_Diseases/Neurological_Disorders/Alzheimer's/
 |OMIM=104300
 |MedlinePlus=000760
 |eMedicineSubj=neuro
 |eMedicineTopic=13
 |MeshID=D000544
 |GeneReviewsNBK=NBK1161
 |Scholia=Q11081
}}

{{Mental and behavioural disorders|selected=neurological}}
{{CNS diseases of the nervous system}}
{{Amyloidosis}}
{{Authority control}}

[[Category:Alzheimer's disease]]
[[Category:Aging-associated diseases]]
[[Category:Ailments of unknown cause]]
[[Category:Amyloidosis]]
[[Category:Aphasias]]
[[Category:Cognitive disorders]]
[[Category:Dementia]]
[[Category:Diseases named after discoverers]]
[[Category:Herpes simplex virus–associated diseases]]
[[Category:Learning disabilities]]
[[Category:Unsolved problems in neuroscience]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia neurology articles ready to translate]]