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Understanding the molecular mechanisms that protect brain function during aging may help reveal novel targets for the development of effective treatments for the memory and cognitive deficits associated with AD. In this study, we analyzed a gene expression dataset generated from the prefrontal cortices of individuals showing no neurological or cognitive abnormalities. The gene expression profiles were used to identify candidate protective genes. We then compared the expression patterns of these genes in aging with their expression patterns in AD, thereby enabling us to pinpoint the genes that potentially contribute to brain resilience that delays or prevents aging-related dementia. We selected seven genes that are potentially protective for aging and AD, and have known homologues in Caenorhabditis elegans (C. elegans). Among these genes, SRPK2, AAK1, EFR3A and MAPK10 were previously implicated in attenuating AD-related cognitive decline. Our experiments demonstrated that all seven genes prioritized by our resilience model significantly extended the lifespan of C. elegans. Given the important relationship between neuronal functional integrity and lifespan (i.e., lifespan vs. brain health span), this work suggests the predicted AD resilience genes could serve as important candidate targets for therapeutic intervention.<\/jats:p>","DOI":"10.3390\/biom16070992","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:56:42Z","timestamp":1783349802000},"page":"992","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Networks and Key Regulators Underlying Resilience of the Human Brain to Aging and Dementia"],"prefix":"10.3390","volume":"16","author":[{"given":"Lei","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Grimaldi","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9171-4962","authenticated-orcid":false,"given":"Minghui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lap","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Shackleton","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Neff","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhidong","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Gandy","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Alzheimer\u2019s Disease Research Center, Icahn School of Medicine at Mount Sinai, 1399 Park Ave, New York, NY 10029, USA"},{"name":"James J Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vahram","family":"Haroutunian","sequence":"additional","affiliation":[{"name":"Nash Family Department of Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Alzheimer\u2019s Disease Research Center, Icahn School of Medicine at Mount Sinai, 1399 Park Ave, New York, NY 10029, USA"},{"name":"James J Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle E.","family":"Ehrlich","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 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New York, NY 10029, USA"},{"name":"Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"},{"name":"Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"ref_1","unstructured":"United States Census Bureau (2018, September 10). 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