Distinguishable effects of Presenilin-1 and APP717 mutations on amyloid plaque deposition

Both APP and PS-1 are causal genes for early-onset familial Alzheimer’s disease (AD) and their mutation effects on cerebral Aβ deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Aβ40 and Aβ42. Aβ isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Aβ42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm2) and area (%) of Aβ42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Aβ40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Aβ burden in a different fashion from APP717 mutations in their familial AD brains.