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More than 100 missense mutations in the presenilin genes PS1 and PS2 have been identified as associated with autosomal-dominant, early-onset (<65 years) Alzheimer disease (AD). Almost all of these mutations alter production of the amyloid-β peptide to increase the proportion of a 42-residue form (Aβ42). Although Aβ42 normally is produced as a minor Aβ variant, this peptide is particularly prone to aggregation and is the major form of Aβ found in AD plaques.
Aβ is generated through the action of two proteases, β- and γ-secretase, the latter determining the length of the peptide and the proportion of Aβ42. Presenilin is apparently the catalytic component of γ-secretase, and the AD-associated mutations in presenilin are thought to alter the bio…