Abstract
Telomere length (TL) is a key indicator of biological aging. Understanding the association between TL and cognitive impairment may provide important insights into disease mechanisms for age-related neurodegenerative disorders, such as Alzheimer disease (AD). However, the relationship between TL and cognitive function remains controversial, with studies reporting positive, negative, or no associations between them. This inconsistency may be attributed to genetic and environmental variations or differences in TL measurement methods. We conducted a comprehensive characterization of DNA-sequence determined telomere length and analyzed its association with cognitive function in the Midwestern Amish. The Midwestern Amish are a founder population demonstrating reduced genetic and environmental variation compared to the general European population. This unique population structure allowed us to better control for potential confounding by non-telomere genetic and environmental factors. Our study confirmed the expected telomere shortening with age and provided both SNP-based and pedigree-based TL heritability estimates. No significant correlation was observed between telomere length and cognitive function. However, a genome-wide association study (GWAS) of TL revealed three loci associated with TL, each containing Amish-enriched rare variants.