Department of Neurology, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan.
Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan, Taiwan.
Dement Geriatr Cogn Disord. 2024;53(3):143-152. doi: 10.1159/000538620. Epub 2024 Apr 1.
The potential influence of age at menarche (AM) on cognitive aging remains inadequate, partly because of the difficulties presented by multiple confounders. To address this issue, Mendelian randomization (MR) analysis was used to explore the causal impacts of AM on cognitive aging.
Using the publicly accessible Taiwan Biobank, we identified single nucleotide polymorphisms (SNPs) significantly associated with AM as instrumental variables to estimate the effects of instruments on cognitive function assessed with the Mini-Mental State Examination (MMSE). We employed several MR methods, including two-stage least squares, inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and constrained maximum likelihood (cML) MR methods, to ensure the stability and reliability of the results.
MR analyses indicated no significant causal relationship between genetically determined AMs and total and subdomain MMSE scores, except the G5 subdomain (βIVW = 0.156, 95% confidence interval [CI]: 0.005, 0.307; βcML = 0.161, 95% CI: 0.014, 0.309). However, in a leave-one-out sensitivity analysis, we found a significant relationship between AM and cognitive aging after eliminating rs157863 and rs6758290, thus demonstrating the potential pleiotropic effects of these two SNPs. After these two SNPs were eliminated, we found a significant causal relationship between AM and overall MMSE scores (βIVW = 0.425, 95% CI: 0.011, 0.839), though.
Evidence from the present MR study did not fully support a causal relationship between AM and cognitive function decline in later life. Potential pleiotropic effects of the genes underlying these two traits are worthy of further investigation.
初潮年龄（AM）对认知衰老的潜在影响尚不清楚，部分原因是存在多种混杂因素的困难。为了解决这个问题，采用孟德尔随机化（MR）分析来探讨 AM 对认知衰老的因果影响。
利用公开的台湾生物库，我们确定了与 AM 显著相关的单核苷酸多态性（SNP）作为工具变量，以估计工具对认知功能的影响，认知功能使用简易精神状态检查（MMSE）进行评估。我们采用了几种 MR 方法，包括两阶段最小二乘法、逆方差加权（IVW）、MR-Egger、加权中位数、加权模式和约束最大似然（cML）MR 方法，以确保结果的稳定性和可靠性。
MR 分析表明，除了 G5 子域（βIVW=0.156，95%置信区间[CI]：0.005，0.307；βcML=0.161，95%CI：0.014，0.309）外，遗传决定的 AM 与总 MMSE 评分和子域 MMSE 评分之间没有显著的因果关系。然而，在一项逐一剔除敏感性分析中，我们发现剔除 rs157863 和 rs6758290 后，AM 与认知衰老之间存在显著关系，表明这两个 SNP 可能存在潜在的多效性效应。剔除这两个 SNP 后，我们发现 AM 与总 MMSE 评分之间存在显著的因果关系（βIVW=0.425，95%CI：0.011，0.839）。
本 MR 研究的证据并未完全支持 AM 与晚年认知功能下降之间存在因果关系。这两个特征背后的基因的潜在多效性效应值得进一步研究。
