Three dimensions of the amyloid hypothesis: time, space and 'wingmen'

Abstract

The amyloid hypothesis, which has been the predominant framework for research in Alzheimer's disease (AD), has been the source of considerable controversy. The amyloid hypothesis postulates that amyloid-β peptide (Aβ) is the causative agent in AD. It is strongly supported by data from rare autosomal dominant forms of AD. However, the evidence that Aβ causes or contributes to age-associated sporadic AD is more complex and less clear, prompting criticism of the hypothesis. We provide an overview of the major arguments for and against the amyloid hypothesis. We conclude that Aβ likely is the key initiator of a complex pathogenic cascade that causes AD. However, we argue that Aβ acts primarily as a trigger of other downstream processes, particularly tau aggregation, which mediate neurodegeneration. Aβ appears to be necessary, but not sufficient, to cause AD. Its major pathogenic effects may occur very early in the disease process.

Figure 1

An updated framework of the amyloid hypothesis. The black arrows illustrate the processing of APP by β- and γ-secretases to yield Aβ species, which subsequently aggregate, ultimately triggering tau aggregation and downstream toxicity. Blue text and arrows illustrate proposed modifiers of the Aβ cascade, while red text and arrows show the influence of aging and comorbid pathologies. Note that several feed-forward cycles are hypothesized, including one involving disturbed sleep promoting Aβ production (and perhaps Aβ clearance, though not depicted), while Aβ aggregation in turn disrupts sleep cycles. Multiple factors, from aging to oxidative stress, contribute to proteostatic failure, which in turn promotes aggregation of Aβ, tau, and likely other toxic proteins. Many of the Aβ modifying factors interact with each other (such as ApoE modulating inflammation) though this is not depicted.