Association of genetic risk score for Alzheimer's disease with late-life body mass index in all of us: Evaluating reverse causation

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-04-06 DOI:10.1002/alz.14598

Minhyuk Choi, Scott C. Zimmerman, Peter T. Buto, Jingxuan Wang, Willa D. Brenowitz, Thomas J. Hoffmann, Adina Zeki Al Hazzouri, Katrina Kezios, M. Maria Glymour

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Abstract

INTRODUCTION

Decreases in body mass index (BMI) may be early consequences of Alzheimer's disease (AD) pathophysiological changes. Previous research in the UK Biobank estimated that AD-related genes began affecting BMI around age 47. We assessed whether this result could be replicated using longitudinal data in an independent cohort.

METHODS

Using All of Us (AOU) (N = 197,619, aged 30+) data, we estimated linear mixed models for associations of Z-scored AD-Genetic Risk Score (AD-GRS) with BMI, stratified by decade of age. We calculated the earliest age at which AD-GRS was associated with differences in BMI using cross-validated models adjusted for demographics.

RESULTS

Higher AD-GRS was statistically associated with lower BMI in participants aged 60–70 (b = −0.060 [−0.113, −0.007]). Best fitting models suggested the inverse association of AD-GRS and BMI emerged beginning at ages 47–54.

DISCUSSION

AD genes accelerate age-related weight loss starting in middle age.

Highlights

Understanding when physiological changes from amyloid pathology begin is key for AD prevention.
Our findings indicate that AD-associated genes accelerate midlife weight loss, starting between 47 and 54 years.
AD prevention research should consider that disease pathology likely begins by middle age.

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阿尔茨海默病遗传风险评分与我们所有人晚年体重指数的关系：评估反向因果关系

简介：体重指数（BMI）的下降可能是阿尔茨海默病（AD）病理生理变化的早期后果。此前在英国生物库（UK Biobank）中进行的研究估计，与阿兹海默症相关的基因在 47 岁左右开始影响体重指数。我们利用独立队列中的纵向数据评估了这一结果是否可以复制。方法我们使用 All of Us (AOU)（N = 197,619 人，年龄在 30 岁以上）的数据，按照年龄的十年分层，估计了 Z 评分的 AD 遗传风险评分（AD-GRS）与 BMI 的关联线性混合模型。我们使用经人口统计学调整的交叉验证模型计算了 AD-GRS 与 BMI 差异相关的最早年龄。结果在 60-70 岁的参与者中，较高的 AD-GRS 与较低的 BMI 在统计学上相关（b = -0.060 [-0.113, -0.007]）。最佳拟合模型表明，从 47-54 岁开始，AD-GRS 与体重指数呈反向关系。讨论 AD 基因从中年开始加速了与年龄相关的体重减轻。亮点了解淀粉样蛋白病理学的生理变化始于何时是AD预防的关键。我们的研究结果表明，AD 相关基因从 47 至 54 岁开始加速中年体重下降。注意力缺失症预防研究应考虑到疾病的病理变化可能始于中年。

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.