Yu Yang, Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, Jilin 130021, China.
J Prev Alzheimers Dis. 2024;11(6):1826-1833. doi: 10.14283/jpad.2024.128.
Aging is one of the most important risk factors for Alzheimer's disease (AD). Biological aging is a better indicator of the body's functional state than age (chronological aging). Leukocyte telomere length (LTL) and epigenetic clocks constructed from DNA methylation patterns have emerged as reliable markers of biological aging. Recent studies have shown that it may be possible to slow down or even reverse biological aging, offering promising prospects for treating AD. Several observational studies have reported an association between biological aging, AD, and cognitive function, but the causality behind this association and the effects of different biological aging markers on AD risk and cognitive function remain unclear. Therefore, we explored the causal relationship between them by Mendelian randomization (MR) study. Inverse-variance weighted (IVW) method is the most dominant analytical method in MR studies, which is a weighted average of estimates from different genotype combinations, and this weighted average provides an overall estimate of the causal effect. The results of the IVW analyses showed that HannumAge acceleration and LTL shortening were able to increase the risk of late-onset AD (LOAD), but not early-onset AD (EOAD). Excellent prospective memory and fluid intelligence are potentially protective against GrimAge acceleration. GrimAge acceleration and HorvathAge acceleration increase the risk of LOAD through effects on LTL. Our findings provide important insights into the role of biological aging in the pathogenesis of AD, while also highlighting the interplay of different biological aging markers and their complexity in different AD subtypes.
衰老是阿尔茨海默病（AD）最重要的危险因素之一。与年龄（实际年龄）相比，生物衰老更能反映身体的功能状态。白细胞端粒长度（LTL）和基于 DNA 甲基化模式构建的表观遗传时钟已成为生物衰老的可靠标志物。最近的研究表明，可能有办法减缓甚至逆转生物衰老，为治疗 AD 带来了有希望的前景。几项观察性研究报告了生物衰老、AD 和认知功能之间的关联，但这种关联的因果关系以及不同生物衰老标志物对 AD 风险和认知功能的影响尚不清楚。因此，我们通过孟德尔随机化（MR）研究来探索它们之间的因果关系。逆方差加权（IVW）法是 MR 研究中最主要的分析方法，它是对不同基因型组合的估计值进行加权平均，而这种加权平均提供了因果效应的总体估计。IVW 分析的结果表明，HannumAge 加速和 LTL 缩短能够增加晚发性 AD（LOAD）的风险，但不能增加早发性 AD（EOAD）的风险。出色的前瞻性记忆和流畅的智力可能有助于预防 GrimAge 加速。GrimAge 加速和 HorvathAge 加速通过影响 LTL 增加 LOAD 的风险。我们的研究结果为生物衰老在 AD 发病机制中的作用提供了重要的见解，同时也强调了不同生物衰老标志物的相互作用及其在不同 AD 亚型中的复杂性。
