Association between Alzheimer's disease-related genes and neurodegenerative blood-based biomarkers in Indian adults.

IF 5.2 2区医学 Q2 GERIATRICS & GERONTOLOGY

Frontiers in Aging Neuroscience Pub Date : 2026-08-19 eCollection Date: 2026-01-01 DOI:10.3389/fnagi.2026.1832155

Hasan Abu-Amara, Wei Zhao, Zheng Li, Yuk Yee Leung, Gerard D Schellenberg, Li-San Wang, Eileen M Crimmins, Bharat Thyagarajan, Masroor Anwar, Perry Hu, Sharmistha Dey, Aparajit B Dey, Xiang Zhou, Kumarasamy Thangaraj, Jinkook Lee, Sharon L R Kardia, Jennifer A Smith

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引用次数: 0

Abstract

Background: Alzheimer's disease (AD) and related dementias are a growing health and economic burden in India. Blood levels of amyloid beta (Ab), tau, and other proteins marking neuronal injury are biomarkers of AD risk and are potentially important for AD prevention.

Methods: In 2,224 participants from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD), we performed gene-based analyses on (1) missense/loss-of-function (LoF) single-nucleotide variants (SNVs) and (2) brain-specific promoter/enhancer SNVs across 84 genes selected from AD GWAS and 25 gene-biomarker pairs selected from biomarker GWAS. We used variant-Set Test for Association using Annotation infoRmation (STAAR) across 7 neurodegenerative biomarkers measured in blood: Ab40, Ab42, Ab42/Ab40, total tau (tTau), tau phosphorylated at threonine 181 (pTau), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). We adjusted for age, sex, and genetic ancestry, with random intercepts for genetic relatedness and biomarker plate. Analyses incorporated weighted annotation scores (e.g., deleteriousness). Significant results (FDR-q < 0.1) were followed up with single variant analysis. Genes were also assessed for sex- and age-interactions using iSKAT.

Results: Missense/LoF variants in 6 AD-associated genes (ECHDC3, CLU, APOE, EPHA1, ICA1L, CASS4) and 1 biomarker-associated gene (APOE) were associated with Ab40, Ab42/Ab40, pTau, and/or GFAP (FDR q < 0.1), with the most significant SNVs tending to be rare/low-frequency (MAF ≤ 0.05) and potentially deleterious. Promoter/enhancer variants in 1 AD-associated gene (CCDC6) were associated with Ab42/Ab40, with the index SNV being a potentially deleterious common variant (MAF = 0.27). Several associated variants appeared to have higher frequency in India compared to other global populations. Missense/LoF SNVs in two AD genes (EPHA1, MS4A6A) had sex-specific effects on Ab42 and/or tTau, and promoter/enhancer SNVs in four AD genes (DGKQ, MS4A6A, MS4A4A, JAZF1) had sex-specific effects on tTau and/or pTau. Missense variants in 12 AD genes and promoter/enhancer variants in two AD genes showed interaction with age on at least one biomarker, primarily GFAP and NfL with genetic effects tending to be stronger at older ages.

Conclusion: Rare and common variants in AD- and neurodegenerative biomarker-associated genes with increased frequency in India compared to other populations may impact blood levels of neurodegenerative biomarkers in South Asians.

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印度成人阿尔茨海默病相关基因与神经退行性血液生物标志物之间的关系

背景：阿尔茨海默病（AD）和相关的痴呆症是印度日益严重的健康和经济负担。血液中β -淀粉样蛋白（Ab）、tau蛋白和其他标记神经元损伤的蛋白水平是阿尔茨海默病风险的生物标志物，对阿尔茨海默病的预防具有潜在的重要意义。方法：在印度纵向衰老痴呆统一诊断评估研究（LASI-DAD）的2224名参与者中，我们进行了基于基因的分析（1)错义/功能丧失（LoF）单核苷酸变异（snv）和(2)从AD GWAS中选择的84个基因和从生物标志物GWAS中选择的25对基因-生物标志物对的脑特异性启动子/增强子snv）。我们利用注释信息（STAAR）对血液中测量的7种神经退行性生物标志物进行变异集关联测试：Ab40、Ab42、Ab42/Ab40、总tau （tTau）、苏氨酸181磷酸化的tau （pTau）、胶质纤维酸性蛋白（GFAP）和神经丝轻链（NfL）。我们调整了年龄、性别和遗传祖先，随机截取遗传相关性和生物标志物板。分析纳入加权注释分数（例如，有害性）。单变量分析结果显著（FDR-q < 0.1）。使用iSKAT还对基因的性别和年龄相互作用进行了评估。结果：6个ad相关基因（ECHDC3、CLU、APOE、EPHA1、ICA1L、CASS4）和1个生物标志物相关基因（APOE）的错sense/LoF变异与Ab40、Ab42/Ab40、pTau和/或GFAP相关（FDR q < 0.1），且最显著的snv倾向于罕见/低频（MAF≤0.05）且具有潜在的危害性。1个ad相关基因（CCDC6）的启动子/增强子变异与Ab42/Ab40相关，SNV指数是潜在有害的常见变异（MAF = 0.27）。与全球其他人群相比，印度的一些相关变异似乎频率更高。两个AD基因（EPHA1、MS4A6A）的错sense/LoF snv对Ab42和/或tTau具有性别特异性作用，四个AD基因（DGKQ、MS4A6A、MS4A4A、JAZF1）的启动子/增强子snv对tTau和/或pTau具有性别特异性作用。12个AD基因的错义变异和2个AD基因的启动子/增强子变异在至少一个生物标志物上显示出与年龄的相互作用，主要是GFAP和NfL，遗传效应在年龄越大越强。结论：与其他人群相比，印度阿尔茨海默病和神经退行性生物标志物相关基因的罕见和常见变异频率增加，可能会影响南亚人神经退行性生物标志物的血液水平。

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来源期刊

Frontiers in Aging Neuroscience GERIATRICS & GERONTOLOGY-NEUROSCIENCES

CiteScore

6.30

自引率

8.30%

发文量

1426

期刊介绍： Frontiers in Aging Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the mechanisms of Central Nervous System aging and age-related neural diseases. Specialty Chief Editor Thomas Wisniewski at the New York University School of Medicine is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.