Ever since Alois Alzheimer dissected his patient’s brain in at the turn of the 20^th century the assumed primary mechanism underlying Alzheimer’s disease (AD) was the proliferation of amyloid protein in the brain with associated destruction of neural tissue and pathways. That focus on amyloid led to the development and recent approval of drugs that act to reduce the amyloid burden in the brain.

However, like every other AD treatment adopted since the turn of this century, those recently developed “breakthrough” anti-amyloid drugs  fall short of the goal of an “effective disease-modifying treatment.” Like the medications in use for decades, they also only inhibit  AD progression by modestly slowing cognitive decline and “turning back the clock of memory loss” for around six months. “Indeed, in the best-case scenario, lowering cerebral Aβ (Beta-amyloid) levels has resulted in some delay of the cognitive decline but it has not arrested the progression to dementia, thus demonstrating an efficacy similar to that of existing therapies (e.g., cholinesterase inhibitors).”¹

The unavoidable conclusion has been that amyloid is not the whole story, and removing it is not a cure. For example, with lequembi, one of the two available anti-amyloid drugs, patients still got worse even when amyloid levels declined or disappeared. Further undermining a singular role for amyloid is the unprecedented retraction in June 2024 of the “landmark” 2006 study naming the specific amyloid protein causing Alzheimer’s disease. That study spawned the dominant hypothesis that “amyloid drives Alzheimer’s” and defined the target for investigation and investment in subsequent anti-amyloid Alzheimer’s therapies. However, key images in that paper were identified as “doctored” by a 2022 investigation, calling into question the foundation underlying the thousands of subsequent papers that had cited (i.e., relied upon) that one. According to some sources, this is the “most cited paper ever retracted.”

The “amyloid cascade” is a widely accepted hypothesis that the neurodegeneration and resultant dementia of AD result from the formation and accumulation of toxic beta-amyloid proteins in our brains. The repudiation by its authors of an article that has provided longstanding support for this theory is surely causing researchers, funders and clinicians to reconsider the amyloid’s role. Increasing interest and resources are turning towards the treatment of Professor Alzheimer’s patient’s second finding, those unusual tangles of tau proteins in the cerebral cortex.

References:

¹Ricciarelli R, Fedele E. The Amyloid Cascade Hypothesis in Alzheimer’s Disease: It’s Time to Change Our Mind. Curr Neuropharmacol. 2017;15(6):926-935.

Arnold, SE, Wolk, DA. Anti-Amyloid Therapies: Progress and Promise. Penn Memory Center 2/7/24  https://www.youtube.com/watch?v=sz-ufCEacBc

Budson A, Solomon P. Memory Loss, Alzheimer’s Disease and Dementia. 3. ed. Elsevier, Inc; 2022

Congdon, E. E., & Sigurdsson, E. M. (2022). Tau-targeting therapies for Alzheimer disease. Nature Reviews Neurology, 18(7), 399-415.

Doggrell SA. Still grasping at straws: donanemab in Alzheimer’s disease. Expert Opin Investig Drugs. Aug 2021;30(8):797-801. doi:10.1080/13543784.2021.19480 10.

Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):352-7. Retraction in: Nature. 2024 Jul;631(8019):240.

Pillar, C.  Authors move to retract discredited Alzheimer’s study.

https://www.science.org/content/article/researchers-plan-retract-landmark-alzheimers-paper-containing-doctored-images

Scott, D. Do we have Alzheimer’s disease all wrong? Vox.com Jun 17, 2024

https://www.vox.com/future-perfect/355108/alzheimers-disease-drug-approval-research-retraction