Mutational Analysis in Early-Onset Familial Dementia in the Japanese Population

Background: Three major causative genes have been implicated as the cause of early-onset familial Alzheimer’s disease (AD): the amyloid precursor protein gene (APP), presenilin-1 (PSEN1) and PSEN2. Although rare, a tau-related dementia with mutations in the microtubule-associated protein tau gene (MAPT) has been identified in patients showing clinical presentations similar to those of AD. Methods: We performed mutational analysis of APP, PSEN1, PSEN2, and MAPT in 10 Japanese families with early-onset dementia clinically diagnosed as probable Alzheimer’s disease. Results: In 4 index patients, we identified 4 missense PSEN1 mutations, namely, L286V, G378E, L381V, and L392V. The mean age at onset in the patients with PSEN1 mutations was 39 years. In 2 families, we found the R406W mutation in MAPT. The mean age at onset of the patients carrying the R406W mutation was 52 years, and they presented with the peculiar AD-like phenotype without apparent behavioral or language problems. Conclusion: These observations suggest that although PSEN1 mutations are the most frequent cause, the MAPT R406W mutation is an important cause of early-onset familial dementia clinically diagnosed as AD. Differentiation of patients with the MAPT mutation from AD patients by genetic testing would be meaningful, considering that a different therapeutic approach should be applied.