With 49 different mutations in the coding region, presenilin 1 (the gene is denoted “PSEN1”; the protein is denoted “psen1”) is the most frequently mutated gene in early onset (onset age! 65 years) Alzheimer disease (AD [MIM 104300])(Sherrington et al. 1995; Cruts and Van Broeckhoven 1998). PSEN1 missense mutations are generally considered fully penetrant mutations. Mostly they are found in patients with a positive family history of early-onset AD compatible with autosomal dominant inheritance. Patients carrying the same mutation usually display very similar onset ages (Van Broeckhoven 1995). An ArG transition at codon 318 in exon 9 of PSEN1, resulting in the nonconserved GlurGly substitution, has been reported, by us (Cruts et al. 1998) and others (Sandbrink et al. 1996; Forsell et al. 1997), in familial AD cases with onset ages of 35–64 years (Cruts and Van Broeckhoven1998). However, segregation of Glu318Gly with AD could not be demonstrated, because either no or too few relatives were available for DNA testing. PSEN1 Glu318Gly involves the last codon of exon 9 and is located in the middle part of the sixth hydrophilic loop of psen1. Because of the high variability in onset age of AD and the mutation’s location in a psen1 region that is less conserved between psen homologues in human and other species, we previously had hypothesized that the Glu318Gly could be either an incompletely penetrant mutation or a rare polymorphism (Cruts and Van Broeckhoven 1998).

To evaluate the frequency of Glu318Gly and its contribution to AD, we screened incident and prevalent demented cases and age-and sex-matched controls derived from the Rotterdam Study. This is a prospective singlecenter population-based study of elderly residents 55 years of age who are from a Rotterdam suburb (Hofman et al. 1991). Cognitive functioning was assessed and diagnosis of dementia made on the basis of the DSM-IIIR definition (American Psychiatric Association 1987). Possible and probable AD was diagnosed according to