{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T22:42:09Z","timestamp":1776292929389,"version":"3.50.1"},"reference-count":71,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,16]],"date-time":"2025-08-16T00:00:00Z","timestamp":1755302400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health\/Fogarty International","award":["R01 AG069013"],"award-info":[{"award-number":["R01 AG069013"]}]},{"name":"National Institutes of Health\/Fogarty International","award":["R-2022-1305-100"],"award-info":[{"award-number":["R-2022-1305-100"]}]},{"DOI":"10.13039\/501100005343","name":"Fundaci\u00f3n IMSS","doi-asserted-by":"publisher","award":["R01 AG069013"],"award-info":[{"award-number":["R01 AG069013"]}],"id":[{"id":"10.13039\/501100005343","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005343","name":"Fundaci\u00f3n IMSS","doi-asserted-by":"publisher","award":["R-2022-1305-100"],"award-info":[{"award-number":["R-2022-1305-100"]}],"id":[{"id":"10.13039\/501100005343","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>While most of the Alzheimer\u2019s disease (AD) cases are sporadic and manifest after age 65 (late-onset AD, LOAD), a subset of patients develop symptoms earlier in life (early-onset, EOAD) due to mutations in the PSEN1, PSEN2, or APP genes with an autosomal-dominant inheritance pattern (AD-EOAD). In this study, we examined the association between age of onset (AoO) and first clinical manifestation (FCM) with the APOE and DAOA genotypes, previously described as modifiers of clinical phenotypes in LOAD and EOAD in 88 individuals clinically diagnosed with AD-EOAD due to the PSEN1 A431E variant (39 females, 49 males). We classified the population according to their genotype (APOE\u03b52, APOE\u03b53, and APOE\u03b54 and DAOA G\/G, G\/A, and A\/A) and FCM (cognitive, behavioral, motor, and memory impaired). Memory impairment was the most frequent symptom (51%), followed by motor disturbances (31.8%), cognitive symptoms other than memory (10.4%), and behavioral changes (6.8%). We found a significant association between APOE genotype and AoO (p &lt; 0.001), with the APOE\u03b54 allele being linked to a delayed onset (\u03b2 = 4.04, SE = 1.11, p = 0.0003). Similarly, individuals with the DAOA rs2391191 A\/A genotype showed a significantly later AoO compared to G\/G carriers (\u03b2 = 2.13, SE = 0.96, p = 0.0301). No significant association was found between APOE or DAOA genotypes and FCM. The findings suggest that both the APOE\u03b54 allele and DAOA rs2391191 A\/A genotype may act as genetic modifiers of AoO, delaying symptom onset in individuals with AD-EOAD. Further research is needed to elucidate the molecular pathways through which APOE and DAOA influence AD-EOAD progression.<\/jats:p>","DOI":"10.3390\/ijms26167929","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T16:22:33Z","timestamp":1755534153000},"page":"7929","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["DAOA and APOE\u03b54 as Modifiers of Age of Onset in Autosomal-Dominant Early-Onset Alzheimer\u2019s Disease Caused by the PSEN1 A431E Variant"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6100-093X","authenticated-orcid":false,"given":"C\u00e9sar A.","family":"Valdez-Gaxiola","sequence":"first","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico"},{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8172-2420","authenticated-orcid":false,"given":"Frida","family":"Rosales-Leycegui","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico"},{"name":"Maestr\u00eda en Ciencias del Comportamiento, Instituto de Neurociencias, Centro Universitario de Ciencias Biol\u00f3gicas y Agropecuarias, Universidad de Guadalajara, Guadalajara 45200, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1011-7155","authenticated-orcid":false,"given":"Abigail","family":"Gaxiola-Rubio","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, Universidad Aut\u00f3noma de Guadalajara, Zapopan 45129, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5858-8978","authenticated-orcid":false,"given":"Sof\u00eda","family":"Dumois-Petersen","sequence":"additional","affiliation":[{"name":"Laboratorio de Ciencias Cl\u00ednicas, CuValles, Universidad de Guadalajara, Ameca 46600, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-1693","authenticated-orcid":false,"given":"Martha Patricia","family":"Gallegos-Arreola","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Ringman","sequence":"additional","affiliation":[{"name":"Alzheimer Disease Research Center, Department of Neurology, Keck School of Medicine at USC, 1520 San Pablo Street Suite 3000, Los Angeles, CA 90033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6096-4579","authenticated-orcid":false,"given":"Luis E.","family":"Figuera","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico"},{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association Report (2024). 2024 Alzheimer\u2019s Disease Facts and Figures. 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