Network‐dependent remote effects and local tau burden jointly shape neuronal dysfunction in Alzheimer's disease

IF 12.8 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2026-10-01 DOI:10.1002/alz.71914

Lukas Frontzkowski,Sebastian Roemer‐Cassiano,Johannes Gnörich,Daniel Janowitz,Hannah Eyob,Katharina Probst,Dario Dhoqina,Anna Dewenter,Anna Steward,Zeyu Zhu,Madleen Klonowski,Fabian Hirsch,Davina Biel,Melina Paulus,Jonathan Vöglein,Sonja Schönecker,Boris‐Stephan Rauchmann,Carolin Kurz,Carolin Koriath,Jan Häckert,Sophia Stöcklein,Carla Palleis,Robert Perneczky,Johannes Levin,Katharina Buerger,Rudolf A. Werner,Günter Höglinger,Matthias Brendel,Nicolai Franzmeier

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引用次数: 0

Abstract

Abstract BACKGROUND Tau pathology in Alzheimer's disease (AD) propagates along the brain's connectome, yet the mechanisms by which tau drives neuronal dysfunction remain unclear. We hypothesized that dysfunction primarily emerges in regions close to tau‐harboring epicenters. METHODS One hundred thirty‐one amyloid‐positive individuals underwent dynamic [ 18 F]PI‐2620 tau positron emission tomography. Kinetic modeling yielded distribution volume ratios (DVRs) and perfusion (R1). Tau epicenters were defined as top 10% DVR regions. Connectivity‐based distance to epicenters was derived from normative resting‐state functional connectivity. RESULTS At the individual level, hypoperfusion was more closely related to distance from tau epicenters than to local tau deposition, particularly in early AD, consistent with diaschisis‐like disconnection. With advancing biological disease severity, local tau deposition increasingly converged with hypoperfusion. Critically, hypoperfusion mediated the relationship between tau accumulation and cognitive decline. DISCUSSION Tau epicenters shape the brain‐wide pattern of neuronal dysfunction, while local tau burden determines the degree of damage driving cognitive decline.

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网络依赖的远程效应和局部tau负担共同塑造阿尔茨海默病的神经元功能障碍

背景：阿尔茨海默病（AD）中的Tau病理学沿着大脑连接组传播，但Tau驱动神经元功能障碍的机制尚不清楚。我们假设功能障碍主要出现在靠近tau -窝藏中心的区域。方法131例淀粉样蛋白阳性个体进行了动态[18 F]PI - 2620 tau正电子发射断层扫描。动力学建模得到分布体积比（DVRs）和灌注（R1）。Tau震中被定义为DVR前10%的区域。基于连通性的震中距离来源于标准静息状态功能连通性。结果：在个体水平上，低灌注与tau中心距离的关系比与局部tau沉积的关系更密切，特别是在AD早期，与分离样断开相一致。随着生物疾病严重程度的提高，局部tau沉积越来越趋向于低灌注。关键的是，低灌注介导了tau积累和认知能力下降之间的关系。Tau中心形成了全脑范围内的神经元功能障碍模式，而局部Tau负担决定了导致认知能力下降的损伤程度。

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

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.