Genetic Variants That Modulate Alzheimer's Disease Risk Deregulate Protein-Protein Correlations in the Gyrus Temporalis Medius

Gerard A Bouland,Niccolo Tesi,Meng Zhang,Andrea B. Ganz,Marc Hulsman,Sven van der Lee, Marieke Graat,Annemieke Rozemuller,Martijn Huisman,Natasja M. van Schoor,Wiesje M. van der Flier,Jeroen Hoozemans,August B. Smit,Marcel J.T. Reinders,Henne Holstege

medrxiv（2025）

Delft University of Technology | Amsterdam UMC | Vrije Universiteit Amsterdam

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Abstract

We conducted a comprehensive protein quantitative trait loci (pQTL) analysis on a unique set of Gyrus Temporalis Medius (GTM) samples obtained from 88 Alzheimer's Disease (AD) patients, 53 non-demented individuals, and 49 cognitively healthy centenarians. This investigation revealed 8,081 genetic variants associated with the abundance of 227 proteins, including several novel variant-protein links not identified in a prior pQTL study of the prefrontal cortex or expression QTL (eQTL) analysis across 12 brain regions (GTEx). Among all the AD risk variants tested for possible pQTL effects, only rs429358-T (which encodes the APOE4 allele) was significantly linked to higher APOE levels in the GTM, potentially explaining why this region is particularly prone to AD pathology. Further, through differential correlation analysis we identified AD risk variants linked to altered protein-protein correlations, specifically rs9381040 in TREML2, rs34173062 in SHARPIN, and rs11218343 near SORL1. Notably, DDX17 appears to play a protective role in individuals with the rs9381040-T/T genotype by tightly regulating synuclein levels. Collectively, these findings demonstrate that AD risk variants disrupt protein-protein interactions, highlighting a genetic basis for the coordinated modulation of protein networks in AD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement No Applicable Funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Medical Ethics Committee of the Amsterdam UMC gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

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【要点】：本研究发现阿尔茨海默病风险遗传变异通过调节蛋白质-蛋白质相互作用影响疾病风险，揭示了疾病遗传基础的蛋白质网络调控机制。

【方法】：研究采用蛋白质定量性状位点（pQTL）分析，对88名阿尔茨海默病患者、53名非痴呆个体和49名认知健康百岁老人的颞中回（GTM）样本进行了分析。

【实验】：通过差异相关性分析，在颞中回样本中识别出与蛋白质-蛋白质相互作用改变的阿尔茨海默病风险变异，使用的数据集为88名阿尔茨海默病患者、53名非痴呆个体和49名认知健康百岁老人的样本，实验结果显示APOE4等位基因编码的rs429358-T与GTM中APOE水平升高显著相关。

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