{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T06:15:00Z","timestamp":1778307300490,"version":"3.51.4"},"reference-count":110,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T00:00:00Z","timestamp":1678233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer\u2019s disease (AD genes). Although the genetics of aging and longevity have been extensively studied, previous studies have focused on a specific set of genes that have been shown to contribute to or are a risk factor for AD. Thus, the connections among the genes involved in AD, aging, and longevity are not well understood. Here, we identified the genetic interaction networks (referred to as pathways) of aging and longevity within the context of AD by using a gene set enrichment analysis by Reactome that cross-references more than 100 bioinformatic databases to allow interpretation of the biological functions of gene sets through a wide variety of gene networks. We validated the pathways with a threshold of p-value &lt; 1.00 \u00d7 10\u22125 using the databases to extract lists of 356 AD genes, 307 aging-related (AR) genes, and 357 longevity genes. There was a broad range of biological pathways involved in AR and longevity genes shared with AD genes. AR genes identified 261 pathways within the threshold of p &lt; 1.00 \u00d7 10\u22125, of which 26 pathways (10% of AR gene pathways) were further identified by overlapping genes among AD and AR genes. The overlapped pathways included gene expression (p = 4.05 \u00d7 10\u221211) including ApoE, SOD2, TP53, and TGFB1 (p = 2.84 \u00d7 10\u221210); protein metabolism and SUMOylation, including E3 ligases and target proteins (p = 1.08 \u00d7 10\u22127); ERBB4 signal transduction (p = 2.69 \u00d7 10\u22126); the immune system, including IL-3 and IL-13 (p = 3.83 \u00d7 10\u22126); programmed cell death (p = 4.36 \u00d7 10\u22126); and platelet degranulation (p = 8.16 \u00d7 10\u22126), among others. Longevity genes identified 49 pathways within the threshold, of which 12 pathways (24% of longevity gene pathways) were further identified by overlapping genes among AD and longevity genes. They include the immune system, including IL-3 and IL-13 (p = 7.64 \u00d7 10\u22128), plasma lipoprotein assembly, remodeling and clearance (p &lt; 4.02 \u00d7 10\u22126), and the metabolism of fat-soluble vitamins (p = 1.96 \u00d7 10\u22125). Thus, this study provides shared genetic hallmarks of aging, longevity, and AD backed up by statistical significance. We discuss the significant genes involved in these pathways, including TP53, FOXO, SUMOylation, IL4, IL6, APOE, and CEPT, and suggest that mapping the gene network pathways provide a useful basis for further medical research on AD and healthy aging.<\/jats:p>","DOI":"10.3390\/ijms24065178","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T03:59:32Z","timestamp":1678247972000},"page":"5178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Genetic Networks of Alzheimer\u2019s Disease, Aging, and Longevity in Humans"],"prefix":"10.3390","volume":"24","author":[{"given":"Timothy","family":"Balmorez","sequence":"first","affiliation":[{"name":"Department of Basic Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Sakazaki","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8806-0611","authenticated-orcid":false,"given":"Shin","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jalz.2018.06.3063","article-title":"Racial and ethnic estimates of Alzheimer\u2019s disease and related dementias in the United States (2015\u20132060) in adults aged \u226565 years","volume":"15","author":"Matthews","year":"2019","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/349704a0","article-title":"Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u2019s disease","volume":"349","author":"Goate","year":"1991","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/375754a0","article-title":"Cloning of a gene bearing missense mutations in early-onset familial Alzheimer\u2019s disease","volume":"375","author":"Sherrington","year":"1995","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/376775a0","article-title":"Familial Alzheimer\u2019s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer\u2019s disease type 3 gene","volume":"376","author":"Rogaev","year":"1995","journal-title":"Nature"},{"key":"ref_5","unstructured":"Sherva, S., and Kowall, N.W. 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