ALZHEIMERS-DISEASE ASSOCIATED WITH MUTATIONS IN PRESENILIN-2 IS RARE AND VARIABLY PENETRANT

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 wer e sought by direct nucleotide sequence analysis of the open reading fr ame of 60 pedigrees with familial Alzheimer's disease (FAD). In the ma jority of these pedigrees, PS-1 and beta-amyloid precursor protein (be ta APP) gene mutations had been excluded. While no additional PS-2 pat hogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observ ed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attrib utable to differences in ApoE genotypes. These results suggest (i) tha t, in contrast to mutations in PS-1, mutations in PS-2 are a relativel y rare cause of FAD; (ii) that other genetic or environmental factors modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.