Interactive Effects of Telomere Length and Genetic Variants on Alzheimer Disease Risk Across Multiple Ancestral Populations

Background: Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. Methods: We estimated TL in whole-genome sequencing data from 35014 Alzheimer's Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6973 persons of European ancestry (EA), 4188 African Americans (AA), 4005 Caribbean Hispanics (CH), and 4170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long and short groups according to the median. An AD GWAS for the interaction of TL with variants having a minor allele count >20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNPxTL interaction term. Results: AD risk was associated with shorter TL (β = -0.18, P < 2x10-16). Longer TL was associated with dosages of APOE ϵ2 (P<5.08x10-8) and APOE ϵ4 (P=2.10x10-2). In the EA group, genome-wide significant (GWS) TLxSNP interactions were identified for variants in SEMA6A (P=1.42x10-8) and LOC105378654 (P=4.17x10-8), between IL15 and INPP4B (P=1.77x10-8) and upstream of RP11-2N5.2 (P=4.60x10-8). In the NAH group, GWS interactions were observed with an intronic variant in BSN (P=3.26x10-8) and missense variant in MST1 (P=3.26x10-8). In the total sample, interactions with variants between CTD-2160D9.1 and EEF1A1P20 (P<1.19x10-8), in TBC1D22A (P=1.06x10-8) and in PLK1 (P=3.28x10-8) were GWS. Conclusion: We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis.