Understanding the role of biological aging on cognitive vulnerability among individuals at risk of Alzheimer’s disease

Abstract

AbstractBackgroundLeukocyte telomere length (LTL) is an objective biomarker of biological aging and has been proposed to play a crucial role in AD progression by impairing cognitive resilience. However, a limited number of studies have evaluated the role of LTL in cognition, showing inconsistent results, particularly in the context of AD pathology. The main objective of this study was to evaluate the association between LTL and cognitive performance in middle‐aged cognitively unimpaired individuals at increased risk of AD.MethodThe study included 1,532 participants from the ALFA cohort. LTL was determined by qPCR in peripheral blood leukocytes. LTL values were log‐transformed, normalized by computing z‐scores and residualized (rLTL) against age and sex using a linear regression model. A cognitive battery was administered to assess verbal memory, psychomotor speed, visual processing, and executive function. Episodic memory (EM), executive function, and global cognitive composites were calculated by averaging normalized raw scores of all subtests in each domain. Generalized linear models were implemented to assess the cross‐sectional association between rLTL and cognitive performance. Association analyses were performed separately in the accelerated aging group (rLTL < percentile 50th) and decelerated aging group (rLTL > percentile 50th). Stratified analyses by sex were conducted.ResultIndividuals at accelerated aging had higher systolic blood pressure and a different distribution of familiar history of AD than those at decelerated aging [Table 1]. Longer rLTL was associated with better performance in the EM domain only among individuals within the accelerated aging group. Remarkably, only free recall measurements remained significant after correction for multiple comparisons. Conversely, longer rLTL was associated with worse psychomotor speed in the whole sample and among individuals in the decelerated group [Table 2]. Women mainly drove these results. Among men, longer rLTL had a beneficial effect on semantic fluency but a detrimental effect on cued recall among those at decelerated aging [Table 3].ConclusionrLTL has a differential effect on cognitive domains among cognitively unimpaired individuals at accelerated/decelerated biological aging. Moreover, results differed depending on sex and cognitive domain. Our results suggest a complex heterogeneity in biological aging mechanisms that appear to change in individuals at increased risk of AD.