Global and regional amyloid-β in explaining APOE-ε4 and sex associations with medial temporal tau: a neuropathology study

IF 10.3 1区医学 Q1 CLINICAL NEUROLOGY

Acta Neuropathologica Pub Date : 2026-10-09 DOI:10.1007/s00401-026-03095-2

Gemma Salvadó, Colin Groot, Laura E. Wisse, Jacob W. Vogel, Thomas G. Beach, Geidy E. Serrano, Eric M. Reiman, Julie A. Schneider, David A. Bennett, Rik Ossenkoppele, Oskar Hansson

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引用次数: 0

Abstract

The medial temporal lobe (MTL) is a key region in Alzheimer’s disease (AD) pathogenesis, affected early by tau pathology. While female sex and APOE-ε4 are two known risk factors that affect tau levels, whether these factors drive tau in the MTL via amyloid-dependent or amyloid-independent mechanisms remains unclear. We investigated these relationships in two large neuropathological cohorts comprising 2550 participants from the Religious Orders Study/Memory and Aging Project (ROS/MAP; n=1587, main cohort) and Arizona Study of Aging and Neurodegenerative Disorders (AZSAND; n=963, replication cohort) covering the whole AD continuum. Neuropathological assessments of global neocortical and regional MTL amyloid-β burden were used to determine the extent to which amyloid-β pathology mediated associations of APOE-ε4 carriership and sex with MTL tau burden. In both cohorts, APOE-ε4 carriership and female sex were associated with significantly greater MTL tau pathology (all p<0.001). Adjustment for global amyloid-β attenuated but did not eliminate these associations (p≤0.024). However, after jointly accounting for global and MTL amyloid-β burden, the association between APOE-ε4 and MTL tau was no longer significant in either cohort (p≥0.19), whereas the association between female sex and MTL tau remained robust (p≤0.004). Models incorporating both global and regional MTL amyloid-β explained substantially more variance in MTL tau burden than models including only global amyloid-β, and results were replicated when further adjusting for diagnostic group or neocortical tau burden. These findings suggest that APOE-ε4 and female sex influence MTL tau accumulation through partially distinct pathogenic pathways, supporting an additional contribution of regional amyloid-β to the APOE-ε4-associated MTL tau burden while implicating additional amyloid-independent mechanisms in female vulnerability to tau accumulation.

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淀粉样蛋白β在解释APOE-ε4和性别与内侧颞叶tau之间的关系：一项神经病理学研究

内侧颞叶（MTL）是阿尔茨海默病（AD）发病的关键区域，早期受到tau病理的影响。虽然女性性别和APOE-ε4是影响tau水平的两个已知危险因素，但这些因素是否通过淀粉样蛋白依赖或淀粉样蛋白非依赖机制驱动MTL中的tau仍不清楚。我们在两个大型神经病理学队列中研究了这些关系，其中包括2550名参与者，来自宗教秩序研究/记忆和衰老项目（ROS/MAP; n=1587，主要队列）和亚利桑那衰老和神经退行性疾病研究（AZSAND; n=963，复制队列），涵盖了整个AD连续体。通过对全球新皮质和区域MTL淀粉样蛋白-β负荷的神经病理学评估，确定淀粉样蛋白-β病理介导APOE-ε4携带者和性别与MTL tau负荷的关联程度。在这两个队列中，APOE-ε4携带者和女性与MTL tau病理显著增加相关（p < 0.001）。总体淀粉样蛋白-β的调整减弱了但没有消除这些关联（p≤0.024）。然而，在综合考虑全球和MTL淀粉样蛋白-β负荷后，APOE-ε4与MTL tau之间的相关性在两个队列中都不再显著（p≥0.19），而女性性别与MTL tau之间的相关性仍然很强（p≤0.004）。包含全球和区域MTL淀粉样蛋白-β的模型比仅包含全球淀粉样蛋白-β的模型更能解释MTL tau负荷的差异，并且在进一步调整诊断组或新皮层tau负荷时，结果是重复的。这些发现表明，APOE-ε4和女性性别通过部分不同的致病途径影响MTL tau的积累，支持了区域淀粉样蛋白-β对APOE-ε4相关MTL tau负担的额外贡献，同时暗示了女性对tau积累易感性的额外淀粉样蛋白独立机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Neuropathologica 医学-病理学

CiteScore

23.70

自引率

3.90%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.