The Causal Relationship between Genetically Predicted Biological Aging, Alzheimer’s Disease and Cognitive Function: A Mendelian Randomisation Study

Y. Hao, W. Tian, B. Xie, X. Fu, S. Wang, Yu Yang
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Abstract

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.

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基因预测的生物衰老、阿尔茨海默病和认知功能之间的因果关系:孟德尔随机研究
衰老是阿尔茨海默病(AD)最重要的风险因素之一。与年龄(计时衰老)相比,生物衰老是人体功能状态的更好指标。白细胞端粒长度(LTL)和根据 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。最近的研究表明,延缓甚至逆转生物衰老是可能的,这为治疗注意力缺失症提供了广阔的前景。一些观察性研究报告了生物衰老、AD 和认知功能之间的关联,但这种关联背后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仍不清楚。因此,我们通过孟德尔随机化(MR)研究探讨了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,这种加权平均提供了对因果效应的总体估计。IVW分析结果显示,HannumAge加速和LTL缩短能够增加晚发AD(LOAD)的风险,但不会增加早发AD(EOAD)的风险。出色的前瞻性记忆和流体智力可能对格林年龄加速具有保护作用。GrimAge加速和HorvathAge加速通过对LTL的影响增加了LOAD的风险。我们的研究结果为了解生物衰老在AD发病机制中的作用提供了重要见解,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。
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The Journal of Prevention of Alzheimer's Disease
The Journal of Prevention of Alzheimer's Disease Medicine-Psychiatry and Mental Health
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9.20
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期刊介绍: The JPAD Journal of Prevention of Alzheimer’Disease will publish reviews, original research articles and short reports to improve our knowledge in the field of Alzheimer prevention including: neurosciences, biomarkers, imaging, epidemiology, public health, physical cognitive exercise, nutrition, risk and protective factors, drug development, trials design, and heath economic outcomes.JPAD will publish also the meeting abstracts from Clinical Trial on Alzheimer Disease (CTAD) and will be distributed both in paper and online version worldwide.We hope that JPAD with your contribution will play a role in the development of Alzheimer prevention.
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