The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics

Abstract

Many drugs targeting amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the US FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate endpoint. The rationale for approval and the extent of the clinical benefit from these antibodies are under intense debate. With the aim of informing this debate, we review clinical trial data for drugs targeting Aβ from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD -Aβ plaques and tau neurofibrillary tangles -and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. Based on this, we propose that Aβ pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe a clinical benefit. We conclude that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of a clinical trial.

Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer’s Disease

“…1A ). We applied a threshold of CL=23.5 to discriminate amyloid accumulators and controls (16,17). We compared the rsfMRI scans acquired at baseline between these groups to assess whether there are changes in BOLD FC prior to longitudinal increases in amyloid load.…”

Autoantibodies targeting neuronal proteins as biomarkers for neurodegenerative diseases

“…Notwithstanding considerable research, currently, there is a lack of consensus if tau Aabs levels are altered in the peripheral circulation of AD and MCI patients. It is important to note that the results of clinical trials with anti-Aβ antibodies leading to the removal of amyloid plaques suggest that neurofibrillary tangle pathology is secondary to the build-up of amyloid deposits, and the reversal of tau pathology might be important in the onset of clinical benefits with cognitive improvements 98 . Currently, it is unclear if anti-tau Aabs have any protective role or can influence the formation of NF tangles, which in turn could influence the spread of tau pathology and cognitive functions.…”

Roles of Syzygium in Anti-Cholinesterase, Anti-Diabetic, Anti-Inflammatory, and Antioxidant: From Alzheimer’s Perspective

“…The multifactorial nature of AD has given rise to various hypotheses based on the pathophysiological and molecular observations in the AD brain. Nevertheless, the amyloid hypothesis is the most widely accepted, given that its deposition is the prime event found in the etiology of AD [ 9 ]. The amyloid burden is highly neurotoxic and inflicts other pathological events, including inflammation, tau phosphorylation, oxidative stress, and mitochondrial damage [ 4 ].…”

“…The amyloid burden is highly neurotoxic and inflicts other pathological events, including inflammation, tau phosphorylation, oxidative stress, and mitochondrial damage [ 4 ]. The ongoing tests on new drug candidates against Aß deposition and tau aggregation show favorable results in animal models but cannot deliver promising effects in clinical trials [ 9 ].…”