Frontotemporal lobar degeneration with MAPT pathogenic variants (
FTLD-MAPT) has heterogeneous tau pathological inclusions postmortem, consisting of three-repeat (3R) or four-repeat (4R) tau
isoforms, or a combination (3R + 4R). Here, we studied grey matter tau burden, its relation to neuronal degeneration, and regional patterns of pathology in different
isoform groups of
FTLD-MAPT. We included 38
FTLD-MAPT autopsy cases with 10 different MAPT pathogenic variants, grouped based on predominant tau
isoform(s). In up to eleven regions (ten cortical and one striatal), we quantified grey matter tau burden using digital histopathological analysis and assigned semi-quantitative ratings for neuronal degeneration (i.e. 0-4) and separate burden of glial and neuronal tau inclusions (i.e. 0-3). We used mixed modelling to compare pathology measures (1) across the entire cohort and (2) within
isoform groups. In the total cohort, tau burden and neuronal degeneration were positively associated and most severe in the anterior temporal, anterior cingulate and transentorhinal cortices.
Isoform groups showed distinctive features of tau burden and neuronal degeneration. Across all regions, the 3R
isoform group had lower tau burden compared to the 4R group (p = 0.008), while at the same time showing more severe neuronal degeneration than the 4R group (p = 0.002). The 3R + 4R group had an intermediate profile with relatively high tau burden along with relatively severe neuronal degeneration. Neuronal tau inclusions were most frequent in the 4R group (p < 0.001 vs. 3R), while cortical glial tau inclusions were most frequent in the 3R + 4R and 4R groups (p ≤ 0.009 vs. 3R). Regionally, neuronal degeneration was consistently most severe in the anterior temporal cortex within each
isoform group. In contrast, the regions with the highest tau burden differed in
isoform groups (3R: striatum; 3R + 4R: striatum, inferior parietal lobule, middle frontal cortex, anterior cingulate cortex; 4R: transentorhinal cortex, anterior temporal cortex, fusiform gyrus). We conclude that
FTLD-MAPT
isoform groups show distinctive features of overall neuronal degeneration and regional tau burden, but all share pronounced anterior temporal neuronal degeneration. These data suggest that distinct
isoform-related mechanisms of genetic
tauopathies, with slightly divergent tau distribution, may share similar regional vulnerability to neurodegeneration within the frontotemporal paralimbic networks.