Abstract
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 35,014 Alzheimer’s Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long (TL > 0) and short (TL ≤ 0) groups. 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 SNP × TL interaction term. RESULTS: AD risk was associated with shorter TL (β = -0.48, P < 2 × 10(–16)). Longer and shorter TL were associated with dosages of APOE ε2 (P = 3.40 × 10(–4)) and ε4 (P = 7.05 × 10(–3)), respectively. In the EA group, genome-wide significant (GWS) TL × SNP interactions were identified for variants in SEMA6A (P = 1.42 × 10(–8)) and LOC105378654 (P = 4.17 × 10(–8)), between IL15 and INPP4B (P = 1.77 × 10(–8)) and upstream of RP11-2N5.2 (P = 4.60 × 10(–8)). In the NAH group, GWS interactions were observed with an intronic variant in BSN (P = 3.26 × 10(–8)) and missense variant in MST1 (P = 3.26 × 10(–8)). In the total sample, interactions with variants between CTD-2160D9.1 and EEF1A1P20 (P < 1.19 × 10(–8)), in TBC1D22A (P = 1.06 × 10(–8)) and in PLK1 (P = 3.28 × 10(–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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02005-8.