Cross-sectional and Mendelian-randomization analyses indicate longer leukocyte telomere length is associated with better cognitive performance and causally linked to lower risk of all-cause dementia, Alzheimer’s and vascular dementia, but show no causal association with Parkinson’s disease.

The study supports telomere length as an aging-related biomarker and possible target for dementia prevention, but provides limited direct, actionable insight for Parkinson’s therapeutic discovery.

This study aimed to investigate the association between telomere length, cognitive function, and dementia, and to assess causality using Mendelian randomization (MR). This study included 1815 participants aged over 60 from the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2002. Cognitive function was assessed using the digit symbol substitution test score, and telomere length was quantified as the mean leukocyte telomere length (telomere/single-copy gene) measured by quantitative polymerase chain reaction. Weighted multivariate linear regression was applied to examine the relationship between cognitive function and telomere length. Additionally, a 2-sample MR approach was employed to explore the genetic causal relationship between telomere length and dementia, and its subtypes, using summary-level genome-wide association studies data derived primarily from individuals of European ancestry. The primary analysis utilized inverse variance weighting, and a series of sensitivity analyses were conducted to ensure robustness of the results. In the cross-sectional observational analysis, longer telomere length was positively associated with higher digit symbol substitution test scores after full adjustment (T2 vs T1: β = 2.1, 95% confidence interval [CI]: 0.35-3.9, P = .022; T3 vs T1: β = 2.5, 95% CI: 0.69-4.3, P < .001). In the MR analysis, genetically predicted longer telomere length was causally associated with a reduced risk of all-cause dementia (odds ratio [OR] per 1-standard deviation increase: 0.90, 95% CI: 0.83-0.98, P = .017), Alzheimer's disease (OR: 0.87, 95% CI: 0.76-0.99, P = .036), and vascular dementia (OR: 0.80, 95% CI: 0.65-0.97, P = .026). However, no causal association was found with frontotemporal dementia or Parkinson's disease. Observational and genetic evidence jointly suggest that longer telomere length is associated with better cognitive function and may play a protective causal role against major forms of dementia.