EPISTATIC EFFECT OF APP717 MUTATION AND APOLIPOPROTEIN-E GENOTYPE IN FAMILIAL ALZHEIMERS-DISEASE

We found a new familial Alzheimer's disease kindred in which the disea se 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 ex pression of the disease and found that in this amyloid precursor prote in-mutated family, ApoE genotype influences the age at onset of the di sease. Three mutated subjects heterozygous for the epsilon 4 allele ha d the earliest age at onset in this family, subjects heterozygous for the epsilon 2 allele had the latest age at onset, and subjects homozyg ous for the epsilon 3 allele had an intermediate age at onset. In this large kindred we also found an amyloid precursor protein-mutated subj ect 2.4 standard deviations older than the mean age at onset without c linical signs and symptoms of the disease and carrying the epsilon 2/e psilon 3 genotype.