E280A PS-1 MUTATION CAUSES ALZHEIMERS-DISEASE BUT AGE-OF-ONSET IS NOTMODIFIED BY APOE ALLELES

A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin-1 (PS 1) gene on chromosome 14 in affected individuals in each of seven Colombian early-onset Alzheimer's diseas e (AD) kindreds. The mutation segregated with disease in kindreds test ed. In the largest kindred (C2), the maximum two-point lod score betwe en the mutation and AD was Z = 8.14 at theta = 0, The presence of a si ngle mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inher ited with AD in all kindreds. These kindreds form the largest collecti on of AD cases with the same PS-1 mutation and the same educational, e nvironmental, and ethnic background in which to study the phenotypic e ffect of putative risk factors, such as the epsilon 4 allele of apolip oprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered, No effect of ApoE g enotype on the age of onset was detected. Previous investigations of t he effect of ApoE genotype on the age of onset were confounded by smal l patient numbers, familial clustering of ApoE genotypes, and combinin g data from unrelated families with different mutations. (C) 1997 Wile y-Liss, Inc.