ESTIMATION OF THE GENETIC CONTRIBUTION OF PRESENILIN-1 AND PRESENILIN-2 MUTATIONS IN A POPULATION-BASED STUDY OF PRESENILE ALZHEIMER-DISEASE

Two closely related genes, the presenilins (PS), located at chromosome s 14q24.3 and 1q42.1, have been identified for autosomal dominant Alzh eimer disease (AD) with onset age below 65 years (presenile AD), We pe rformed a systematic mutation analysis of all coding and 5'-non-coding exons of PS-1 and PS-2 in a population-based epidemiological series o f 101 unrelated familial and sporadic presenile AD cases, The familial cases included 10 patients of autosomal dominant AD families sampled for linkage analysis studies, In all patients mutations in the amyloid precursor protein gene (APP) had previously been excluded, Four diffe rent PS-1 missense mutations were identified in six familial cases, tw o of which where autosomal dominant cases, Three mutations resulted in onset ages above 55 years, with one segregating in an autosomal domin ant family with mean onset age 64 years (range 50-78 years), One PS-2 mutation was identified in a sporadic case with onset age 62 years, Ou r mutation data provided estimates for PS-1 and PS-2 mutation frequenc ies in presenile AD of 6 and 1% respectively. When family history was accounted for mutation frequencies for PS-1 were 9% in familial cases and 18% in autosomal dominant cases, Further, polymorphisms were detec ted in the promoter and the 5'-non-coding region of PS-1 and in intron ic and exonic sequences of PS-2 that will be useful in genetic associa tion studies.