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.

具有MAPT致病性变异的额颞叶变性(FTLD-MAPT) 在死后具有异质的 tau 病理内含物，由三重复 (3R) 或四重复 (4R) tau 亚型或组合 (3R + 4R) 组成。在这里，我们研究了 FTLD-MAPT 不同亚型组的灰质 tau 负荷、它与神经元变性的关系以及病理区域模式。我们纳入了 38 例 FTLD-MAPT 尸检病例和 10 种不同的MAPT致病性变异，根据主要的 tau 异构体分组。在多达 11 个区域（10 个皮质和 1 个纹状体），我们使用数字组织病理学分析量化了灰质 tau 负荷，并指定了神经元变性的半定量评级（即 0-4）和神经胶质和神经元 tau 包涵体的单独负荷（即 0 –3). 我们使用混合模型来比较病理学测量 (1) 整个队列和 (2) 亚型组内。在整个队列中，tau 负荷和神经元变性呈正相关，并且在前颞叶、前扣带回和经内嗅皮质中最为严重。异构体组显示出 tau 负荷和神经元变性的独特特征。在所有地区，与 4R 组相比，3R 亚型组的 tau 负荷较低（p = 0.008)，同时显示出比 4R 组更严重的神经元变性 ( p  = 0.002)。3R + 4R 组具有相对较高的 tau 负荷和相对严重的神经元变性的中间特征。神经元 tau 包涵体在 4R 组中最常见（p  < 0.001 与 3R），而皮质神经胶质 tau 包涵体在 3R + 4R 和 4R 组中最常见（p ≤ 0.009 对比 3R)。在区域上，神经元变性在每个亚型组的前颞叶皮层中始终最为严重。相反，tau 负荷最高的区域在亚型组中不同（3R：纹状体；3R + 4R：纹状体、顶叶下小叶、中额叶皮质、前扣带回皮质；4R：经内嗅皮质、前颞叶皮质、梭状回）。我们得出结论，FTLD-MAPT 同工型组显示出整体神经元变性和区域 tau 负荷的独特特征，但都具有明显的前颞神经元变性。这些数据表明，tau 基因病的不同亚型相关机制，tau 蛋白分布略有不同，可能在额颞旁边缘网络内对神经变性具有相似的区域脆弱性。