Microtubule associated protein tau p.R406W patient carriers present with a nonconforming clinical phenotype

Abstract

AbstractBackground MAPT p.R406W is an autosomal dominantly inherited missense mutation associated with FTLD with an amnestic, AD‐like phenotype. Our group first described a carrier pedigree (labeled ADG) in 2003, with 47 relatives.We aim to delineate phenotypic and genetic characteristics of MAPT p.R406W carriers through 19‐year follow‐up, and to provide first data on mutation frequency in FTD and AD.MethodWe extended the ADG pedigree, obtained data over 19 years on symptoms, biomarkers and neuropathology. Furthermore, we screened FTD (n=647) and AD (n=1100) patient cohorts for new carriers.ResultThe ADG family now counts 38 mutation carriers. 7 unrelated carriers were identified in AD and FTD cohorts. Inclusion of additional relatives procured 56 mutation carriers (39 affected).p.R406W mutation frequencies were 0.62% (FTD) and 0.27% (AD). All probands shared genetic kinship, suggesting a common 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)) emerged. bvFTD patients had significantly worse prognosis. Disinhibition/aggression were highly common (100% of bvFTD, 40% of AD patients). CSF amyloid‐β1‐42 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.ConclusionWe are first to report MAPT p.R406W mutation frequencies, unexpectedly high in FTD ànd AD. Contrary to previous reports, we observed a unique phenotypic shift in Belgian p.R406W carriers, with prominent behavioral symptoms, as well as memory decline. Surprisingly, CSF biomarkers showed decreased amyloid‐β1‐42, and neuropathology was FTLD‐tau with isolated 3R‐tau, highly unusual findings for this tauopathy.