At least 30 different missense mutations have been identified within the presenilin 1 (PS1) gene in pedigrees transmitting familial Alzheimer's disease. The authors investigated the clinical and pathological features of affected members of two pedigrees segregating a PS1 Met146Leu mutation. Genetic relationships between these pedigrees can be effectively excluded on the basis of genealogical data and the fact that although the amino acid substitution is identical, the nucleotide mutations are different. The clinical picture shows remarkable similarities in the neurological and the neuropathological findings between the two pedigrees. This general clinical and pathological concordance argues that much of the disease phenotype arises directly from the effects of the amino acid substitution within the PS1 protein itself. Clinical differences could arise from a direct effect of the difference in base sequence or, alternatively, from the effect of genetic or environmental modifiers.