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

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.