[Progress of the molecular genetic analysis for Alzheimer's disease]

The pathogenesis of Alzheimer's disease (AD) remains unclear. We ascertained 57 Japanese families with early onset familial Alzheimer's disease (EOFAD; mean onset age < 65 years). Screening the known beta/A4 amyloid precursor protein (APP) mutations in familial AD by a simplified PCR product detection system disclosed only one EOFAD with the APP717Val-Ile mutation (AD1 locus). Four of 6 families showing a positive linkage to AD3 locus had four different mutations on the presenilin 1 gene. These mutations were Val 96 Phe, Ile223Thr, His163Arg and splicing mutation with an AG-AA substitution at the acceptor site of intron 9. The allele frequency of APOE-e4 of late-onset and early-onset AD was significantly higher than that of age-matched controls (p < 0.0001). These results suggest that APOE-e4 (AD2 locus) is a susceptibility gene for AD in the Japanese population, regardless of the age at onset. It is probable that the risk for AD in most subjects is likely to arise from the cumulative effects of environmental factors along with various genetic factors. Advances in molecular biology and molecular genetics have enabled us to more easily understand these genetic factors.