The amyloid hypothesis on trial

Abstract

I n early 2018, two high-profile clinical trials of drugs for Alzheimer's disease ended in disappointment. The drugs joined a long list of potential treatments that have failed to deliver significant benefits in people. Their development was guided by an idea that has dominated research on Alzheimer's disease for more than 25 years: the amyloid hypothesis, which is the assumption that accumulation of the peptide amyloid-β is the main cause of the condition. Researchers proposed that when amyloid-β clumps together to form deposits in the brain, it triggers neurodegenerative processes that lead to the loss of memory and cognitive ability that is observed in Alzheimer's disease. Amyloid-β is therefore an obvious therapeutic target-if you can deal with the peptide, then you can treat the condition. The amyloid hypothesis has never been universally accepted, and the failed drug trials have only emboldened its critics. "It's led to a mixture of some careful thinking and recriminations about whether the right things have been done, " says John Hardy, a neurogeneticist at University College London, and a pioneer of the hypothesis. He and many other researchers remain undeterred, however. "We're all disappointed, but there are concrete reasons why each failure occurred, " says Dennis Selkoe, a neurologist at Harvard Medical School in Boston, Massachusetts. These might be as simple as the drugs being administered too late With the continued failure of potential drugs for Alzheimer's disease, is it time to look beyond amyloid-β as the root cause of the condition?

Spatial and temporal transcriptomics reveal microglia-astroglia crosstalk in the amyloid-β plaque cell niche of Alzheimer’s disease

“…The advent of these new technologies allows tackling in a novel way a central question in AD research, i.e., what is the relationship of amyloid plaques to the neurodegenerative process in brain? The question is particularly relevant given the emerging insight and worry that amyloid lowering therapies show little efficacy with regard to memory improvement (Gallardo and Holtzman, 2017;Makin, 2018). Some investigators have suggested that the plaques are inert and that soluble oligomeric Aβ drives neurotoxicity (Glabe, 2008;Ono, Condron and Teplow, 2009;Mucke and Selkoe, 2012).…”

Peptid‐basierte molekulare Strategien zum Einsatz bei Proteinfehlfaltung, Proteinaggregation und Zelldegeneration

“…Tatsächlich werden solche Einwände derzeit intensiv diskutiert. [60] Andererseits gibt es überwältigende Evidenz für eine Schlüsselrolle des Amyloidbildungsprozesses bei der Pathogenese relevanter Krankheiten. [4] Die Fehlschläge in den klinischen Studien kçnnten daher auch darauf hinweisen, dass die Kandidatenmoleküle ihre Zielstrukturen nicht früh genug oder effektiv erreichen konnten.…”

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

“…As a result, considerable resources have been expended over the past forty years in searching for therapeutics to treat AD, all of which have failed—sometimes repeatedly—in late‐stage clinical trials (Khachaturian, ; Martin, ; Morris, Clark, & Vissel, ; Mullane & Williams, ; Panza et al., ). Among the reasons for these failures are: (i)The politicization of AD, which has tended to confuse the guidelines for the diagnosis and treatment of a disease that is increasingly viewed as multifactorial and non‐linear in both causality and progression (De Strooper & Karran, ; Medina, Khachaturian, Rossor, Avila, & Cedazo‐Minguez, ).…”

“…As a result, considerable resources have been expended over the past forty years in searching for therapeutics to treat AD, all of which have failed-sometimes repeatedly-in late-stage clinical trials (Khachaturian, 2018;Martin, 2018;Morris, Clark, & Vissel, 2018;Mullane & Williams, 2018a;Panza et al, 2019). Among the reasons for these failures are:…”