A LOCUS segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21 (ref. 1), close to the amyloid precursor protein (APP) gene^2–5. Recombinants between the APP gene and the AD locus have been reported^6–8 which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous⁹. Families with late-onset AD do not show linkage to chromosome 21 markers^9,10. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not^8,9,11. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD^8,9. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val→Ile) close to the carboxy terminus of the β-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.