Kernel reposted this
The concept of resilience in Alzhiemer’s disease (AD) is a highly contested subject that I hope more experts weigh in on. Ryan Field's post highlights an important and often overlooked concept when applying precision medicine tactics to trial design for neurodegenerative disease: precisely segmenting based on both biological and cognitive symptoms. There are only two ongoing trials I’m aware of that are recruiting preclinical AD patients (not necessarily "resilient" per se): TRAILBLAZER-ALZ-3 sponsored by Eli Lilly and Company (NCT05026866) and AHEAD-3-45 sponsored by Eisai US (NCT04468659). At first glance, these trials seem to have narrow inclusion criteria around biological and clinical staging (which is great applied precision neuromedicine in action!), but it’s not clear to me how patients’ clinical stages (cognitive state) are being tracked over time (see Table from the paper Ryan Field highlights in his post) In these ongoing trials, it’s also not clear to me whether patients are being segmented based on the clinical stage according to the matrix Ryan shared, but I’d imagine that the readouts from these interventional studies between 2027 and 2030 will be quite informative for the field at large, especially if more detail about the clinical stage of each patients and their progression are both tracked closely. More studies like this are needed and better tools for precisely measuring cognition will accelerate this and make segmenting based on clinical stage easier. I’m proud of the work the Kernel is doing to develop better cognitive measures for patients with MCI. This field of medicine has a lot to gain from the transdisciplinary collaboration between biopharma and companies pushing the frontiers of informative, multi-modal data gathering like Kernel.
Last week, just before #WorldAlzheimersDay, I joined the Alzheimer's Association®'s #AAICAdvancements: Modernizing Diagnosis Meeting (#ADdx24). The main focus of the meeting was to bring together clinicians, industry, and academia to discuss the latest updates to the diagnostic framework for AD. Both biological and clinical staging are important but currently one has better tools to measure than the other - can you guess which?!?! The 2024 update to the guidance for diagnosing AD clearly defines the disease through a combination of the clinical and biological staging (link in comments). A lot of focus was placed on the emerging tools for biological staging, like pTau217, but not so much focus was spent on how to accurately perform clinical staging. The clinical staging guidelines have remained largely unchanged since 2011! The 2D matrix describing the Alzheimer's staging is outlined in Table 7 (below) The clinical stages map to: 0: Genetically Determined AD 1: Cognitively Unimpaired 2: Subjective Cognitive Decline (SCD) 3: Mild Cognitive Impairment (MCI) 4-6: Mild, Moderate, and Severe Dementia While there were many fantastic sessions and posters, I found one of the most interesting sessions at #ADdx24 to be the final discussion, "Can Blood Tests Stand Alone in Alzheimer's Disease Diagnosis?". Some interesting points that came up are: - Biomarker testing is not currently recommended for anyone without cognitive symptoms. - Pre-test probabilities are important in biomarker positive/negative predictive value and can be driven by factors like age and cognitive status. - A specialist clinician is needed to make a determination between SCD (Stage 2) and MCI (Stage 3). - Specialist clinicians are less than 75% accurate in diagnosing MCI (Stage 3). - Wait times to see a specialist range from 2-12 months depending on where you live. - The gray diagonal in the integrated biological + clinical staging table is the "expected progression" of biomarkers and clinical effects. Right of the diagonal is explained by co-pathologies. To the left of the diagonal are individuals who show resilience to the disease pathology. This resilient group is currently poorly understood. - Resilience can have a significant impact on clinical trial outcomes when resilient individuals are randomized to the placebo group. It is clear that Alzheimer's diagnostics are advancing and #biomarker tests are continuing to improve. There is also a clear need for better clinical measures of cognitive impairment and dementia. I'm excited about the work we're doing at Kernel to build objective clinical measures of brain function that relate directly to cognitive decline. We can also help solve some of today's challenges in drug development, like resilience! I look forward to continuing our work to advance the field so we can create better outcomes for patients with #Alzheimers. Special shoutout to Phyllis Ferrell for being the most enthusiastic poster visitor.