Alzheimer's disease associated with mutations in presenilin 2 is rare and variably penetrant

Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 weresought by direct nucleotide sequence analysis of the open reading frame of60 pedigrees with familial Alzheimer's disease (FAD). In the majority ofthese pedigrees, PS-1 and beta-amyloid precursor protein (beta APP) genemutations had been excluded. While no additional PS-2 pathogenic mutationswere detected, four silent nucleotide substitutions and alternativesplicing of nucleotides 1338-1340 (Glu325) were observed. Analysis ofadditional members of a pedigree known to segregate a Met239Val mutation inPS-2 revealed that the age of onset of symptoms is highly variable (range45-88 years). This variability is not attributable to differences in ApoEgenotypes. These results suggest (i) that, in contrast to mutations inPS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that othergenetic or environmental factor modify the AD phenotype associated withPS-2 mutations; and (iii) that still other FAD susceptibility genes remainto be identified.