Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by the accumulation of TAR-DNA-binding protein 43 (TDP-43) aggregates in older adults. LATE coexists with Lewy body disease (LBD) as well as other neuropathological changes including Alzheimer’s disease (AD). We aimed to identify the pathological, clinical, and genetic characteristics of LATE in LBD (LATE-LBD) by comparing it with LATE in AD (LATE-AD), LATE with mixed pathology of LBD and AD (LATE-LBD + AD), and LATE alone (Pure LATE). We analyzed four cohorts of autopsy-confirmed LBD (n = 313), AD (n = 282), LBD + AD (n = 355), and aging (n = 111). We assessed the association of LATE with patient profiles including LBD subtype and AD neuropathologic change (ADNC). We studied the morphological and distributional differences between LATE-LBD and LATE-AD. By frequency analysis, we staged LATE-LBD and examined the association with cognitive impairment and genetic risk factors. Demographic analysis showed LATE associated with age in all four cohorts and the frequency of LATE was the highest in LBD + AD followed by AD, LBD, and Aging. LBD subtype and ADNC associated with LATE in LBD or AD but not in LBD + AD. Pathological analysis revealed that the hippocampal distribution of LATE was different between LATE-LBD and LATE-AD: neuronal cytoplasmic inclusions were more frequent in cornu ammonis 3 (CA3) in LATE-LBD compared to LATE-AD and abundant fine neurites composed of C-terminal truncated TDP-43 were found mainly in CA2 to subiculum in LATE-LBD, which were not as numerous in LATE-AD. Some of these fine neurites colocalized with phosphorylated α-synuclein. LATE-LBD staging showed LATE neuropathological changes spread in the dentate gyrus and brainstem earlier than in LATE-AD. The presence and prevalence of LATE in LBD associated with cognitive impairment independent of either LBD subtype or ADNC; LATE-LBD stage also associated with the genetic risk variants of TMEM106B rs1990622 and GRN rs5848. These data highlight clinicopathological and genetic features of LATE-LBD.

边缘系统为主的年龄相关性 TDP-43 脑病 (LATE) 的特征是老年人中 TAR-DNA 结合蛋白 43 (TDP-43) 聚集体的积累。LATE 与路易体病 (LBD) 以及包括阿尔茨海默病 (AD) 在内的其他神经病理学变化并存。我们旨在通过与 AD 晚期 (LATE-AD)、LATE 和 AD 混合病理学 (LATE-LBD + AD) 进行比较来确定 LATE LATE (LATE-LBD) 的病理、临床和遗传特征，和单独的 LATE（Pure LATE）。我们分析了四组经尸检证实的 LBD ( n  = 313)、AD ( n  = 282)、LBD + AD ( n  = 355) 和衰老 ( n = 111）。我们评估了 LATE 与患者概况的关联，包括 LBD 亚型和 AD 神经病理学改变 (ADNC)。我们研究了 LATE-LBD 和 LATE-AD 之间的形态和分布差异。通过频率分析，我们对 LATE-LBD 进行了分期，并检查了与认知障碍和遗传风险因素的关联。人口统计学分析显示，在所有四个队列中，LATE 与年龄相关，LATE 的频率在 LBD + AD 中最高，其次是 AD、LBD 和衰老。LBD 亚型和 ADNC 与 LBD 或 AD 中的 LATE 有关，但与 LBD + AD 中无关。病理分析显示 LATE 的海马分布在 LATE-LBD 和 LATE-AD 之间存在差异：与 LATE-AD 相比，在 LATE-LBD 中，神经元细胞质内含物在 cornu ammonis 3 (CA3) 中更常见，并且在 LATE-LBD 中，主要在 CA2 到下托中发现了由 C 末端截短的 TDP-43 组成的丰富的精细神经突，而这不是和 LATE-AD 一样多。其中一些细小的神经突与磷酸化的 α-突触核蛋白共定位。LATE-LBD 分期显示 LATE 神经病理学变化比 LATE-AD 更早地在齿状回和脑干中扩散。LBD 中 LATE 的存在和流行与认知障碍相关，与 LBD 亚型或 ADNC 无关；LATE-LBD 阶段也与遗传风险变异有关 LATE-LBD 分期显示 LATE 神经病理学变化比 LATE-AD 更早地在齿状回和脑干中扩散。LBD 中 LATE 的存在和流行与认知障碍相关，与 LBD 亚型或 ADNC 无关；LATE-LBD 阶段也与遗传风险变异有关 LATE-LBD 分期显示 LATE 神经病理学变化比 LATE-AD 更早地在齿状回和脑干中扩散。LBD 中 LATE 的存在和流行与认知障碍相关，与 LBD 亚型或 ADNC 无关；LATE-LBD 阶段也与遗传风险变异有关TMEM106B rs1990622 和GRN rs5848。这些数据突出了 LATE-LBD 的临床病理学和遗传特征。