{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T13:36:57Z","timestamp":1792417017059,"version":"4.4.0"},"reference-count":58,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Proyectos de Impulso a la Investigaci\u00f3n","award":["PIN 2024-V"],"award-info":[{"award-number":["PIN 2024-V"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background: Early-onset Alzheimer\u2019s 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\u2013control 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\u2013Weinberg 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 (&lt;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.<\/jats:p>","DOI":"10.3390\/medsci14020228","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T12:20:25Z","timestamp":1777551625000},"page":"228","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regulatory Variation at TERT and TERC Shows Limited Association with Early-Onset Alzheimer\u2019s Disease in Carriers of the Mexican Founder Mutation PSEN1 A431E"],"prefix":"10.3390","volume":"14","author":[{"given":"Celeste Patricia","family":"Gazc\u00f3n-Rivas","sequence":"first","affiliation":[{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8713-3089","authenticated-orcid":false,"given":"Iliannis Yisel","family":"Roa-Bruz\u00f3n","sequence":"additional","affiliation":[{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Instituto de Investigaci\u00f3n en Ciencias Biom\u00e9dicas, Departamento de Cl\u00ednicas M\u00e9dicas, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9443-7905","authenticated-orcid":false,"given":"Luis F\u00e9lix","family":"Duany-Almira","sequence":"additional","affiliation":[{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar Aly","family":"Vald\u00e9z-Gaxiola","sequence":"additional","affiliation":[{"name":"Programa de Doctorado en Gen\u00e9tica Humana, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"},{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Centro M\u00e9dico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5858-8978","authenticated-orcid":false,"given":"Sofia","family":"Dumois-Petersen","sequence":"additional","affiliation":[{"name":"Centro Universitario de los Valles, Departamento de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 46708, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Eduardo","family":"Figuera-Villanueva","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente (CIBO), Centro M\u00e9dico Nacional de Occidente (CMNO), Instituto Mexicano del Seguro Social (IMSS), Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5963-9712","authenticated-orcid":false,"given":"Antonio","family":"Quintero-Ramos","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Inmunolog\u00eda, Departamento de Fisiolog\u00eda, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9851-8961","authenticated-orcid":false,"given":"Carmen Magdalena","family":"Gurrola-D\u00edaz","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Enfermedades Cr\u00f3nico Degenerativas, Centro Universitario de Ciencias de la Salud (CUCS), Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7443-2514","authenticated-orcid":false,"given":"Daniel","family":"Ortu\u00f1o-Sahagun","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4940-022X","authenticated-orcid":false,"given":"Yeminia","family":"Valle","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias Traslacionales, Departamento de Neurociencias, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9982-7571","authenticated-orcid":false,"given":"Oscar","family":"Arias-Carri\u00f3n","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Neurociencias Cl\u00ednica, Instituto Nacional de Rehabilitaci\u00f3n Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico"},{"name":"Tecnol\u00f3gico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City 14380, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","unstructured":"Huang, X. 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