{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:17:07Z","timestamp":1789661827557,"version":"4.0.1"},"reference-count":78,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["5R01DA052271"],"award-info":[{"award-number":["5R01DA052271"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R21DA060111"],"award-info":[{"award-number":["1R21DA060111"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["1R61AG086971"],"award-info":[{"award-number":["1R61AG086971"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurology International"],"abstract":"<jats:p>Background\/Objectives: Alzheimer\u2019s disease (AD) is defined by amyloid-\u03b2 plaques and tau neurofibrillary tangles and is typically associated with progressive cognitive decline. However, a substantial subset of individuals remains cognitively intact despite intermediate-to-high AD pathology, a phenomenon termed cognitive resilience. This review aims to synthesize genetic variants and biological pathways associated with preserved cognition in the presence of AD neuropathology. Methods: We performed a narrative thematic synthesis of human genetic studies (GWAS, sequencing, biomarker-informed cohorts) and extreme resilience case reports. Variants were prioritized by replication, mechanistic plausibility, and relevance to clinicopathologic dissociation, and were organized by shared biological pathways. When applicable, cognitive resilience was operationalized using residual-based approaches modeling cognitive performance after adjustment for neuropathological burden, age, sex, and education or cognitive reserve proxies reported by each cohort. Results: Recurrent resilience-associated variants include APOE \u03b52, APOE3-Christchurch, RELN-COLBOS, ATP8B1, RAB10, PLCG2, PICALM, CLU, FN1, and synapse-linked markers such as NPTX2. These variants converge on lipid metabolism, synaptic function and neuroplasticity, tau regulation and proteostasis, immune and inflammatory signaling, vascular\/BBB resilience, and RNA regulation. Conclusions: Genetic determinants of cognitive resilience highlight mechanisms that preserve neural integrity independent of pathological load. Targeting resilience pathways may enable precision therapies designed to maintain cognitive function in AD.<\/jats:p>","DOI":"10.3390\/neurolint18030050","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T12:48:56Z","timestamp":1772542136000},"page":"50","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Architecture of Cognitive Resilience in Alzheimer\u2019s Disease: Mechanisms, Pathways, and Therapeutic Implications"],"prefix":"10.3390","volume":"18","author":[{"given":"Gabriel","family":"Burdman","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"},{"name":"College of Arts, Sciences and Education, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1716-4928","authenticated-orcid":false,"given":"Juliet","family":"Akkaoui","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Colon","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"},{"name":"College of Arts, Sciences and Education, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"},{"name":"College of Arts, Sciences and Education, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madepalli K.","family":"Lakshmana","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100065","DOI":"10.1016\/j.nbas.2023.100065","article-title":"Cognitive resilience and severe Alzheimer\u2019s disease neuropathology","volume":"3","author":"Ahangari","year":"2023","journal-title":"Aging Brain"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Barnett, E.J., Hess, J.L., Hou, J., Escott-Price, V., Fennema-Notestine, C., Kremen, W., Lin, S.J., Zhang, C., Gaiteri, C., and Elman, J. 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