Genetic modifiers of APOE-ε4-associated cognitive decline

Authors

• Alex G. Contreras, Vanderbilt University
• Skylar Walters, Vanderbilt University
• Jaclyn M. Eissman, Vanderbilt University
• Derek B. Archer, Vanderbilt University
• Alexandra N. Regelson, Vanderbilt University
• Alaina Durant, Vanderbilt University
• Michelle Clifton, Vanderbilt University
• Subhabrata Mukherjee, University of Washington
• Michael L. Lee, University of Washington
• Seo Eun Choi, University of Washington
• Phoebe Scollard, University of Washington
• Emily H. Trittschuh, University of Washington
• Jesse Mez, Boston University School of Medicine
• William S. Bush, Case Western Reserve University School of Medicine
• Brian W. Kunkle, University of Miami
• Carlos Cruchaga, Washington University School of Medicine in St. Louis
• Adam C. Naj, Perelman School of Medicine
• Katherine A. Gifford, Vanderbilt University
• Murat Bilgel, National Institutes of Health (NIH)
• Amanda B. Kuzma, Perelman School of Medicine
• Balebail Ashok Raj, University of South Florida
• Kristin Fargher, University of South Florida
• Amanda Smith, University of South Florida
• Lisa Raudin, Cornell University
• Gloria Chaing, Cornell University

Abstract

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4–associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Document Type

Article

Publication Date

2-20-2026

Notes/Citation Information

Publisher Copyright: © The Author(s) 2026.

Digital Object Identifier (DOI)

10.1038/s41467-026-68933-z

Archival?

Archival

Repository Citation

Contreras, Alex G.; Walters, Skylar; Eissman, Jaclyn M.; Archer, Derek B.; Regelson, Alexandra N.; Durant, Alaina; Clifton, Michelle; Mukherjee, Subhabrata; Lee, Michael L.; Choi, Seo Eun; Scollard, Phoebe; Trittschuh, Emily H.; Mez, Jesse; Bush, William S.; Kunkle, Brian W.; Cruchaga, Carlos; Naj, Adam C.; Gifford, Katherine A.; Bilgel, Murat; Kuzma, Amanda B.; Raj, Balebail Ashok; Fargher, Kristin; Smith, Amanda; Raudin, Lisa; and Chaing, Gloria, "Genetic modifiers of APOE-ε4-associated cognitive decline" (2026). Epidemiology and Environmental Health Faculty Publications. 116.
https://uknowledge.uky.edu/epidemiology_facpub/116