Fig. 1.

The amyloid hypothesis. According to the current ‘amyloid cascade’ model of disease causation, Aβ overproduction stems from the disruption of homeostatic mechanisms that regulate the proteolytic cleavage of APP under physiological conditions. This model proposes that age-related, genetic, epigenetic and environmental factors collude to provoke a metabolic shift favouring the processing of APP by BACE1 and the intramembranous γ-secretase complex composed in part by presenilin-1 or presenilin-2, while simultaneously inhibiting the physiological, secretory pathway via α-secretase, which releases soluble APPα which precludes generation of Aβ. The net result is to enhance the production of the putatively neurotoxic Aβ₄₂ monomer at the expense of the putatively neuroprotective Aβ₄₀. The current version of the amyloid hypothesis claims that Aβ₄₂ accumulation into soluble oligomers is the primary driver of neuropathology, although the data allow for an independent or synergistic role for insoluble fibrils