Table 1.

Summary of evidence supporting increased amyloid β-peptide (Aβ) or Aβ42/Aβ40 in the pathogenesis of presenilin mutations

Alzheimer disease (AD)-causing amyloid precursor protein (APP) mutations increase Aβ or Aβ42/Aβ40.

Triplication of the APP gene, either alone or with all of chromosome 21, leads to AD.

Brain Aβ42 deposits are observed early and presymptomatically in trisomy 21

Presenilin is the catalytic component of γ-secretase, produces Aβ and determines the carboxy-terminal length of Aβ peptides.

AD-causing presenilin mutations increase Aβ42/Aβ40; the fact that presenilin and APP mutations cause AD by a common mechanism is parsimonious and logical, as presenilin cleaves APP to produce Aβ.

No AD-associated mutations have been found in any other γ-secretase substrate besides APP.

Among more than 100 AD-causing mutations in presenilins, complete loss of function of a single allele has not been found.

The Ihara model of processive proteolysis of APP by γ-secretase points to a biochemical mechanism by which a less-efficient protease (reduction of function) can lead to an increase in Aβ42/Aβ40 (gain of function).