Abstract Body: Introduction: Stroke, dementia, and late-life depression (LLD) are age-related brain diseases that pose significant public health challenges. Leukocyte telomere length (LTL), a proposed marker of biological age influenced by a complex interplay of both lifestyle and heritable factors, may offer valuable insights into the modifiability of risk for these diseases. We aimed to study the association between LTL and these three outcomes, and whether healthy lifestyle choices modify this risk.
Methods: We utilized data from the UK Biobank (UKB), including participants with valid LTL measurements. We accounted for modifiable lifestyle risk factors with the Brain Care Score (BCS), a 21-point metric validated in the UKB for age-related brain diseases. We used a modified 19-point BCS adapted to available UKB data. LTL measurements were divided into tertiles to examine associations with incident stroke, dementia, and LLD, with shortest LTL serving as reference. Kaplan-Meier curves assessed the relationship between LTL tertiles and outcomes. Cox proportional hazards models adjusted for age, sex, and a 5-point higher baseline BCS provided adjusted hazard ratios (HR). To meet the proportional hazards assumption, we stratified the Cox model into three age groups (<50, 50–59, and ≥60). A Mendelian Randomization (MR) framework was employed to investigate causal relationships between LTL and these diseases.
Results: The analysis included 356,173 participants, with an average age of 56.97 years, of whom 46.31% were male. Kaplan-Meier plots showed associations between longer LTL and lower incidence rates for all conditions. The Cox model confirmed these findings: stroke HRs for intermediate and longest LTL tertiles were 0.89 (95%CI: 0.85-0.94) and 0.87 (95%CI: 0.83-0.92); dementia HRs were 0.86 (95%CI: 0.81-0.91) and 0.77 (95%CI: 0.72-0.82); and LLD HRs were 0.94 (95%CI: 0.90-0.97) and 0.88 (95%CI: 0.84-0.91). Interaction terms between BCS and LTL were non-significant, suggesting limited lifestyle modification of LTL-mediated risks. MR analysis showed no significant causal associations between LDL and these diseases.
Conclusions: Longer LTL is linked to reduced risks of stroke, dementia, and LLD, independent of lifestyle factors measured by BCS. These findings emphasize LTL's complex role in age-related brain diseases and underscore the need for research into exposures influencing LTL, potentially elucidating new interventions or improved tools for risk prediction.