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Using data from 3007 participants in the National Institute on Aging Late-Onset Alzheimer\u2019s Disease Family Study (NIA-LOAD GWAS), we conducted a family-based GWAS of eight quantitative cognitive phenotypes encompassing episodic memory (Logical Memory IA and IIA), working memory (Digit Span Forward, Backward, and Ordering), and semantic fluency (Animal, Fruit and Vegetable, and Vegetable Fluency). Family-based association testing in PLINK v1.9 identified numerous single nucleotide polymorphisms (SNPs) associated with cognitive phenotypes at genome-wide significant (p &lt; 5 \u00d7 10\u22128) levels. Notably, genome-wide significant variants with cognatic functions were localized to genes implicated in synaptic function, neurodevelopment, and neurodegeneration, including TOMM40 (rs2075650), ERBB4 (rs1521543), APLP2 (rs12281267, rs959354), PTPRD (rs1353983, rs970347, rs1392511), NCAM2 (rs2826728), GRM7 (rs6788201), PAX5 (rs2988003, rs2381595), NRG1 (rs16875655), and NRG3 (rs1937957). Furthermore, the TOMM40 (rs2075650) was significantly associated with AD as a binary outcome (p = 4.60 \u00d7 10\u221224) and APLP2 (rs12281267, rs959354), APOE (rs405509), PTPRD (rs1353983, rs970347, rs1392511) were associated with AD (p &lt; 0.001). Additionally, several pathways including the ERBB4 signaling pathway (adjusted p = 2.82 \u00d7 10\u22123), driven by ERBB4, NRG1, and NRG3 may contribute to cognitive impairments. This study provides a comprehensive resource of cognitive endophenotype associations in AD families, advancing understanding of the genetic architecture underlying memory, executive function, and cognitive aging, and highlights new therapeutic targets for replication and functional follow-up.<\/jats:p>","DOI":"10.3390\/cimb48050442","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T08:08:02Z","timestamp":1777018082000},"page":"442","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Family-Based GWAS of Cognitive Endophenotypes Reveals Genetic Architecture of Memory and Executive Function in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7118-3877","authenticated-orcid":false,"given":"Kesheng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Biobehavioral Health & Nursing Science, College of Nursing, University of South Carolina, Columbia, SC 29208, USA"},{"name":"South Carolina SmartState Center for Healthcare Quality, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6788-0688","authenticated-orcid":false,"given":"Xueying","family":"Yang","sequence":"additional","affiliation":[{"name":"South Carolina SmartState Center for Healthcare Quality, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA"},{"name":"Department of Health Promotion, Education and Behavior, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2451-4888","authenticated-orcid":false,"given":"Gayenell","family":"Magwood","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health & Nursing Science, College of Nursing, University of South Carolina, Columbia, SC 29208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7893-6341","authenticated-orcid":false,"given":"Chun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Health and Biomedical Sciences, College of Health Affairs, University of Texas Rio Grande Valley, Brownsville, TX 78520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Osvaldo","family":"Navia","sequence":"additional","affiliation":[{"name":"Division of Geriatrics and Palliative Medicine, John W. 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