From longitudinal follow-up over 19 years, we obtained data on clinical characteristics as well as neuropathology. We investigated the potential modifying effect of the MAPT H1/H2 and the APOE genotypes on the phenotype.

Of 55 carriers, 39 were symptomatic. Allele and haplotype sharing analysis confirmed a genetic kinship among all, suggesting a common ancestor. Average onset age and disease duration were 59.8 and 12.7 years (ranges 40-75, 5-25). The most frequent clinical diagnoses were dementia (unspecified) (43.6%), AD (28.2%) and behavioral variant frontotemporal dementia (bvFTD) (25.6%). Presenting symptoms commonly included disinhibition and behavioral problems in all groups (72.7%). Remarkably, CSF biomarker profiles often showed decreased Aβ1-42 and Aβ_1-42/ Aβ_1-40 ratio, and elevated P-tau and T-tau. Neuropathology was FTLD-tau. We observed a significantly shorter disease duration in carriers of an APOE ε4 allele compared to non-carriers.

We observed a nonconforming clinical phenotype of MAPT p.R406W carriers in the Flemish-Belgian cohort with 25.6 % presenting a bvFTD phenotype. Contrary to previous reports, prominent behavioral symptoms were highly frequent in the entire cohort (72.7%). CSF biomarkers, on the other hand, commonly showed AD-like abnormalities. The presence of an APOE ε4 allele shortened disease duration significantly.