Background: Early-onset Alzheimer’s disease (EOAD) caused by autosomal dominant mutations provides a deterministic framework for investigating genetic modifiers of neurodegeneration. Telomere biology has emerged as a central regulator of genomic stability, cellular ageing, and stress response integration, yet its role in EOAD, particularly in under-represented populations, remains poorly defined. Methods: We conducted a cross-sectional case–control study to evaluate the genetic distribution, disease association, and predicted regulatory consequences of common variants in the telomere maintenance genes TERT and TERC in individuals from Western Mexico. The EOAD group comprised genetically confirmed carriers of the PSEN1 p.Ala431Glu (A431E) founder mutation with clinical EOAD (n = 69), and controls were unrelated individuals without dementia (n = 179). Five common variants were analyzed: rs2242652, rs2853677, rs2736100, and rs10069690 (TERT), and rs12696304 (TERC). Results: Genotype distributions in controls conformed to the Hardy–Weinberg equilibrium. Single-variant analyses showed no significant allele-level associations. Most TERT variants did not show significant allele-level associations with EOAD. However, a preliminary genotype-level enrichment for the GC allele at rs12696304 (TERC) was observed among EOAD cases compared with controls; allele-level associations were not significant. Linkage disequilibrium analysis revealed low r² values (<0.20), supporting variant independence. Population-level allele frequency comparisons revealed ancestry-dependent divergence across loci; in silico functional annotation localised all variants to non-coding regulatory regions. GTEx-based analyses indicated that rs12696304 acts as an eQTL for ACTRT3 in whole blood and pituitary, as well as for LRRC34 in the cerebellar hemisphere, suggesting a potential regulatory network within the TERC locus (3q26.2). Conclusions: Overall, common regulatory variants in TERT did not show strong independent effects on EOAD susceptibility in PSEN1 A431E carriers. However, the convergence of association patterns, functional annotation, and regulatory evidence provides hypothesis-generating support for the TERC locus (3q26.2), particularly rs12696304, as a candidate region for further investigation. Additional studies integrating telomere dynamics, functional validation, and multi-omics analyses are needed to clarify the role of telomere biology in the pathogenesis of autosomal dominant EOAD.

Background/Objectives: Alzheimer’s disease (AD) exhibits marked genetic heterogeneity between early-onset (EOAD) and late-onset (LOAD) forms. EOAD is typically associated with highly penetrant variants, whereas LOAD follows a polygenic architecture dominated by non-coding variation. However, the tissue-specific regulatory consequences of these variants remain insufficiently characterized. This study aimed to compare the regulatory genomic architectures underlying EOAD and LOAD using a multi-tissue integrative approach. Methods: GWAS-associated variants for EOAD and LOAD were retrieved from the GWAS Catalog using a relaxed significance threshold (p < 1 × 10⁻⁵). Variants were functionally annotated and integrated with GTEx v8 eQTL data across 13 neurologically relevant tissues and peripheral blood. Regulatory effects were evaluated using eQTL slope estimates. Basal gene expression patterns were assessed using GTEx RNA-seq data, and protein–protein interaction and functional enrichment analyses were performed using the STRING database. Results: A total of 287 variants were analyzed (32 EOAD, 255 LOAD), with minimal overlap. EOAD exhibited a highly focal regulatory profile, identifying GSE1 as the sole eQTL-regulated gene, restricted to the dorsolateral prefrontal cortex (BA9). In contrast, LOAD displayed a broad multi-tissue regulatory architecture involving APH1B, APOE, CEP63, and HAVCR2, with heterogeneous tissue-specific effects. LOAD-regulated genes converged on pathways related to γ-secretase activity, amyloid precursor protein processing, and Notch signaling, whereas GSE1-associated interactions were enriched for chromatin organization and epigenetic repression. Conclusions: EOAD and LOAD exhibit distinct regulatory genomic architectures, with EOAD characterized by focal, region-specific regulation and LOAD by widespread, tissue-dependent effects, highlighting stage-specific molecular mechanisms contributing to AD heterogeneity.