were identified in 1996, in the genes that encode the γ-secretase proteins presenilin 1 and presenilin 2 , which affect the location at which γ-secretase cuts APP. The mutations favour the production of longer variants of amyloid-β that clump together more readily. This seeds the accumulation of amyloid-β into larger structures called oligomers. Further accumulation produces insoluble fibrils, which then aggregate into the plaques characteristic of Alzheimer’s disease.
The weak degree to which plaque burden correlates with disease severity has also been used to criticise the amyloid hypothesis. Cognitive symptoms are linked more closely to the number and location of tau tangles than they are to the same characteristics of amyloid-β plaques. Furthermore, evidence from post-mortem examinations indicates that such tangles often occur in the absence of plaques.