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

Abstract

<i>Background:</i> Three major causative genes have been implicated as the cause of early-onset familial Alzheimer’s disease (AD): the amyloid precursor protein gene <i>(APP)</i>, presenilin-1 <i>(PSEN1)</i> and <i>PSEN2</i>. Although rare, a tau-related dementia with mutations in the microtubule-associated protein tau gene <i>(MAPT)</i> has been identified in patients showing clinical presentations similar to those of AD. <i>Methods:</i> We performed mutational analysis of <i>APP</i>, <i>PSEN1</i>, <i>PSEN2</i>, and <i>MAPT</i> in 10 Japanese families with early-onset dementia clinically diagnosed as probable Alzheimer’s disease. <i>Results:</i> In 4 index patients, we identified 4 missense <i>PSEN1</i> mutations, namely, L286V, G378E, L381V, and L392V. The mean age at onset in the patients with <i>PSEN1</i> mutations was 39 years. In 2 families, we found the R406W mutation in <i>MAPT</i>. 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. <i>Conclusion:</i> These observations suggest that although <i>PSEN1</i> mutations are the most frequent cause, the <i>MAPT</i> R406W mutation is an important cause of early-onset familial dementia clinically diagnosed as AD. Differentiation of patients with the<i> MAPT</i> mutation from AD patients by genetic testing would be meaningful, considering that a different therapeutic approach should be applied.