Does excess brain amyloid doom a person to dementia? Amazingly, in one recent study, amyloid-positive subjects showed cognitive recovery after performance worsening. The authors state that the cognitive declines were associated with the study BACE inhibitor drug. Ironically, the drug was created to help prevent dementia, but had been stopped for toxicity reasons. There were about 500 total subjects in the trial, age about 70.
SO, these amyloid baby boomers had the wherewithal to bounce back after the agent was stopped!
The Journal of Alzheimer’s Disease graciously posted my opinion viewpoint last week, in which I discuss some details (with wishful thinking about learning from the failure, especially trying to learn from the subjects’ recovery and resilience, along with links to the paper in JAMA and other resources):
https://www.j-alz.com/editors-blog/posts/bace-fascinating-failures-one-cognitive-recovery
Background (not in the JAD piece):
The path from precursor protein to amyloid beta, with cleaving enzymes [Beta Amyloid precursor Cleaving Enzyme, hence BACE], is shown above. Experimental agents known as BACE inhibitors have been designed to slow the accumulation and presumed toxicity of amyloid beta in brains. At least three have failed in clinical trials, all three were associated with cognitive worsening.
To be fair, in a 2020 cognitive followup of subjects in two other BACE inhibitor trials, namely verubecestat and lanabecestat, there were some subscore improvements on the study. Overall, though, both agents “…failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer’s disease”
BTW, Dr. David Knopman of Mayo (2019) did write in NEJM about “informative failures” in AD trials, but it’s unclear that this cognitive recovery data was known then. He concludes: “To be blunt, Aβ [amyoid beta] lowering seems to be an ineffective approach, and it is time to focus on other targets to move therapeutics for Alzheimer’s disease forward.”
Cognitive Resilience or Reserve or Resistance have been concepts articulated for years, and are still being refined, for example: Montine (2019), Latimer (2019), and Yao (2020). Perhaps “This Is The Way” [silly Mandolorian reference].
