Delineate phenotypic and genetic characteristics of Belgian MAPT p.R406W carriers through 19-year clinical follow-up, and provide first data on mutation frequency in FTD and AD patients.

MAPT p.R406W is an autosomal dominantly inherited missense mutation associated with frontotemporal lobar degeneration (FTLD) with an amnestic, AD-like phenotype. Our group described a Belgian carrier pedigree (labeled ADG) in 2003, with 47 family members.

We extended the ADG pedigree. We obtained data over 19 years on their clinical characteristics, biomarkers and neuropathology. Furthermore, we screened FTD (n = 647) and AD (n = 1100) patient cohorts for p.R406W.

The ADG family now counts 38 mutation carriers. 4 unrelated carriers were identified in AD and FTD patient cohorts. Inclusion of additional family members generated a total cohort of 56 mutation carriers (39 affected).

Mutation frequency of p.R406W was 0.62% in FTD and 0.27% in AD. All probands shared genetic kinship, suggesting a common Belgian ancestor.

Average onset age and disease duration were 60.9 and 12.4 years (ranges 54-69, 5-25). Remarkably, two distinct phenotypes (clinical AD (n = 10) or bvFTD (n = 9)) were present. bvFTD patients had worse prognosis, with significantly earlier onset and death. Neuropsychiatric symptoms, like disinhibition/aggression, were highly common (100% of bvFTD, 40% of clinical AD patients). CSF amyloid-β 1-42 was decreased in all 5 patients with CSF data, 2/5 with concomitant tau elevation. Neuropathology was FTLD-tau, notably showing only 3R tau isoforms.

We are first to report mutation frequencies of MAPT p.R406W, unexpectedly high in both FTD ànd AD. Contrary to previous reports, we observed a unique phenotypic shift in Belgian p.R406W carriers with prominent behavioral symptoms and 47.4% with bvFTD. Surprisingly, CSF biomarkers consistently showed decreased amyloid-β 1-42, and neuropathology was FTLD-tau with isolated 3R tau, both highly unusual findings for this tauopathy.