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

Many drugs that target amyloid-beta(A beta) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-A beta antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate end point. 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 that target A beta from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD-A beta plaques and tau neurofibrillary tangles - and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. On this basis, we propose that A beta pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (similar to 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.