Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease

We found a new familial Alzheimer's disease kindred in which the disease cosegregates with the APP717Val‐→Ile mutation and in which all of the three most common apolipoprotein E (ApoE) alleles are represented. We studied the relationship between ApoE genotype and the clinical expression of the disease and found that in this amyloid precursor protein‐mutated family, ApoE genotype influences the age at onset of the disease. Three mutated subjects heterozygous for the ϵ4 allele had the earliest age at onset in this family, subjects heterozygous for the ϵ2 allele had the latest age at onset, and subjects homozygous for the ϵ3 allele had an intermediate age at onset. In this large kindred we also found an amyloid precursor protein‐mutated subject 2.4 standard deviations older than the mean age at onset without clinical signs and symptoms of the disease and carrying the ϵ2/ϵ3 genotype.