The beta-site of beta-amyloid precursor protein cleaving enzyme (BACE) cleaves the beta-amyloid (Abeta) precursor protein at the N-terminal end of Abeta, allowing for the production of Abeta by C-terminal gamma-secretase cleavage. We hypothesized that over-activity of BACE might lead to the overproduction of Abeta, hence causing Alzheimer's disease (AD). Molecular genetic analyses of BACE in 9 autosomal dominant AD families and a population-based sample of 101 presenile AD cases did not identify genetic linkage, pathogenic mutations or genetic association with BACE, suggesting that BACE is not genetically involved in the etiology of AD.