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

Abstract

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.

Clinical and Neuroimaging Characterization of Chinese Dementia Patients with <b><i>PSEN1</i></b> and <b><i>PSEN2</i></b> Mutations

“…In Japanese patients, epidemiologic and genetic studies of Alzheimer's dementia did not find any mutations in PSEN2 and PSEN1 [19]. Another study in 10 Japanese early-onset familial dementia patients showed that the most common mutations were in the PSEN1 gene with no mutations found in the PSEN2 gene [20]. We were unable to confirm whether these variants segregate with disease status because of a lack of available family members to test (all of the relatives with a history of AD or FTD of the patients of interest were deceased at the time of the study).…”

Characterization of the Brain β-Amyloid Isoform Pattern at Different Ages of Tg2576 Mice

“…The 82E1 antibody has been well characterized as human A ␤ N-terminal specific. It reacts with both soluble and fibrillar A ␤ to a similar degree and does not cross-react with mouse A ␤ [25] . The creators of the NU-4 antibody suggest that the NU-4 epitope is three-dimensional, in which aggregation of A ␤ 1-28 to form a dimer is necessary to align correct amino acids in the binding pocket, perhaps several from each single peptide.…”

Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease

“…Pedigrees were considered to have an FAD by at least one first-degree relative with clinical features indicative of dementia. Six of the 12 EO-FAD families in which missense mutations in PSEN1 (L286V, G378E, L381V and L392V) or MAPT (R406W) were found in our previous study9 were excluded from the further genetic study, because the genetic causes of their AD have been identified. This study was approved by the Institutional Review Board of Niigata University.…”