Health & Biomedical Sciences Faculty Publications
Document Type
Article
Publication Date
4-23-2026
Abstract
Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive memory and cognitive decline. Conventional genome-wide association studies (GWAS) comparing AD cases and controls may miss genetic influences that act along a continuum of cognitive function. Using data from 3007 participants in the National Institute on Aging Late-Onset Alzheimer’s 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 < 5 × 10−8) 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 × 10−24) and APLP2 (rs12281267, rs959354), APOE (rs405509), PTPRD (rs1353983, rs970347, rs1392511) were associated with AD (p < 0.001). Additionally, several pathways including the ERBB4 signaling pathway (adjusted p = 2.82 × 10−3), 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.
Recommended Citation
Wang, K., Yang, X., Magwood, G., Xu, C., Navia, R. O., Neils-Strunjas, J., & Li, X. (2026). Family-Based GWAS of Cognitive Endophenotypes Reveals Genetic Architecture of Memory and Executive Function in Alzheimer’s Disease. Current Issues in Molecular Biology, 48(5), 442. https://doi.org/10.3390/cimb48050442
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Publication Title
Current Issues in Molecular Biology
DOI
10.3390/cimb48050442
Comments
© 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.