Physical inactivity in preclinical Alzheimer's disease: Risk factor, early symptom, or both?

IF 7.4 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2026-09-05 eCollection Date: 2026-07-01 DOI:10.1002/trc2.70316

Jiawei Zhao, Xin Li, Mengxuan Wu, Zhanjun Zhang

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引用次数: 0

Abstract

Physical inactivity is a key modifiable risk factor for Alzheimer's disease (AD). However, emerging evidence suggests a bidirectional relationship where inactivity also serves as an early manifestation of AD pathology. This perspective synthesizes recent findings from long-term epidemiological cohorts, brainstem neuropathology, and digital phenotyping to reconceptualize the role of inactivity in preclinical AD. Early tau accumulation in catecholaminergic nuclei (locus coeruleus and ventral tegmental area) disrupts circuits essential for reward valuation and effort calculation. We hypothesize that this neurobiological failure may manifest as prodromal apathy and declining physical activity years before cognitive impairment. Standard metrics like step counts fail to capture these nuances. We propose a multidimensional digital phenotype - incorporating temporal complexity, circadian rhythms, and life-space mobility - to distinguish "behavioral" from "biologically constrained" inactivity. This framework has critical implications for trial enrichment and the design of personalized lifestyle interventions.

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临床前阿尔茨海默病的缺乏运动：危险因素，早期症状，还是两者兼而有之？

缺乏运动是阿尔茨海默病（AD）的一个关键可改变的危险因素。然而，新出现的证据表明一种双向关系，即不活动也可以作为AD病理的早期表现。这一观点综合了来自长期流行病学队列、脑干神经病理学和数字表型的最新发现，重新定义了不活动在临床前AD中的作用。儿茶酚胺能核（蓝斑和腹侧被盖区）的早期tau积累破坏了奖励评估和努力计算所必需的回路。我们假设这种神经生物学上的失败可能表现为前驱性冷漠和身体活动的减少，而在认知障碍发生前几年。步数等标准指标无法捕捉到这些细微差别。我们提出了一种多维数字表型——结合时间复杂性、昼夜节律和生活空间流动性——来区分“行为”和“生物约束”的不活动。这一框架对试验的丰富和个性化生活方式干预的设计具有重要意义。

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 and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.