Alzheimer's Disease: The Amyloid Cascade Hypothesis Turns 30
Krzysztof Potempa
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2022 marks 30 years since Professor John Hardy and Gerald Higgins published a theory that provides a foundation for our current understanding of Alzheimer’s disease (1).
The amyloid hypothesis remains unproven yet it catches the collective imagination to become, with the passage of time, so seductive that it dominates peer review opinion and arrests the development of alternative ideas (2). For example, alternative hypotheses must explain: 1) why amyloid toxicity is not the etiology of Alzheimer's disease (AD); 2) what alternative mechanisms cause the degeneration and dementia of AD, and 3) why increased amyloid accumulates in the brain in AD (3)
Phase III Clinical Trials of agents targeting amyloid in AD
11 of 15 potential therapeutics intended to target the role of Aβ in Alzheimer in various ways, have been tested in phase III trials and have clearly failed to demonstrate clinical efficacy. The 12 Aβ targeting agents terminated at phase III include in Alzheimer disease: Tramiprosate, Tarenflurbil, Semagacestat, Bapineuzumab, Gammagard, Solanezumab, Gantenerumab, Verubecestat, Atabecestat, Lanabecestat, Crenezumab, Elenbecestat, Umibecestat, Amilomotide (4).
For a field that has seen nearly every trial fail, the flop of yet another expensive Phase III candidate is hardly unexpected. Nor is the subsequent debate over what, exactly, the data mean for the amyloid cascade hypothesis that triggers neurodegeneration (5)
Expert thoughts on the amyloid hypothesis
“Collectively, these results prove the amyloid hypothesis is scientifically correct. Indeed, greater focus might have enabled the field to achieve this breakthrough for patients earlier than now”-Dennis Selkoe, one of the major promoters of the amyloid hypothesis (13)
“Are we are going to tie up the whole field for another 15 to 20 years?”-George Perry?(6)
“There are a lot of ideas out there that are reasonably well-supported, but very few people work on. Some of those might be more important than we think. There’s not an awful lot more to be added to the amyloid hypothesis. The time to cast a wider net is now — we need a bigger base of ideas”-Michael Murphy (6)
“The evidence in favour of the amyloid hypothesis is, for me overwhelming. And I say that as someone who has never worked on amyloid. More than anything else, we very urgently need a diversification of target development”-Simon Lovestone (5)
“He was always saying amyloid was rubbish. We used to get on stage to debate each other and then go to the bar. The disagreement [with Mark Smith, a vocal amyloid opponent] was good because we did different experiments, and although we were denigrating each other’s work, that’s how we led to progress.”-John Hardy about Mark Smith from Case Western Reserve University (10). Sadly, Mark Smith was killed in a hit-and-run accident by Daniel Neesham, 50, while walking home from a tavern near his house in December 2010. Mark was a director of basic science research of CWRU's Memory and Cognition Center, co-editor-in-chief of the Journal of Alzheimer's Disease and executive director of the American Aging Association. (10)
Twenty Years of the Alzheimer's Disease Amyloid Hypothesis
"It is conceivable that at some point in this century, a genetically personalized medical approach—following strict legal safeguards—will exploit genetics-based findings to guide both prediction of disease risk and advanced drug development to effectively treat and prevent this formidable disease. (7)"-Rudy Tanzi and Lars Bertram
The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics
"Four scenarios that describe the potential role of amyloid-β in AD are described: amyloid-β trigger; amyloid-β threshold; amyloid-β driver; and amyloid-β irrelevant. Whether current and future amyloid-β-centric therapeutics will show clinical efficacy will crucially depend on which of these scenarios most accurately reflects the AD process (11)
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Resolving controversies on the path to Alzheimer’s therapeutics
"It would be fair to our patients and their families if some of the lay press coverage of issues arising in Alzheimer’s disease research became more measured and less provocative. Although new findings from preclinical research or early clinical trials can seem exciting, they rarely deserve front-page coverage before their full importance for the human disorder has been established"-Dennis Selkoe (12)
The case for rejecting the amyloid cascade hypothesis
"Instead of rejecting the hypothesis, the field has essentially redefined the disease. The result is a dangerous circular logic that is holding back the field. It has been proposed that if people have plaques in their brain but are cognitively normal, they nonetheless have an early, ‘preclinical’ stage of AD"-Karl Herrup (8)
The amyloid hypothesis of Alzheimer's disease at 25 years
“It is not a question of one hypothesis against another. Rather, we must pursue multiple approaches, leading to a range of therapeutics that may together prevent the looming personal and societal tragedy that Alzheimer’s disease has become.”-Dennis Selkoe and John Hardy (9)
The Amyloid Hypothesis on Trial
Future directions
Designed Immunotherapies in Alzheimer‘s Disease
2 个月No mentioning of a real alternative Amyloid Beta hypothesis, the Beta Amyloid Dysfunction (BAD)hypothesis. In contrast to the cascade hypothesis, the disease mechanism is now defined by disturbance of essential physiological Amyloid Beta monomer turnover. The BAD hypothesis can explain positive and negative results of all clinical candidates so far. https://doi.org/10.3389/fnins.2019.01154