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. 2026 Feb 20.
doi: 10.1038/s41467-026-68933-z. Online ahead of print.

Genetic modifiers of APOE-ε4-associated cognitive decline

Alex G Contreras  1   2 , Skylar Walters  1 , Jaclyn M Eissman  1   2 , Derek B Archer  1   2 , Alexandra N Regelson  1 , Alaina Durant  1 , Michelle Clifton  1 , Subhabrata Mukherjee  3 , Michael L Lee  3 , Seo-Eun Choi  3 , Phoebe Scollard  3 , Emily H Trittschuh  4   5 , Jesse Mez  6 , William S Bush  7 , Brian W Kunkle  8 , Carlos Cruchaga  9   10 , Adam C Naj  11   12 , Katherine A Gifford  1 , Murat Bilgel  13 , Amanda B Kuzma  12 ; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC); Alzheimer’s Disease Sequencing Project (ADSP); Michael L Cuccaro  8 , Margaret A Pericak-Vance  8 , Lindsay A Farrer  6   14   15 , Li-San Wang  12 , Gerard D Schellenberg  12 , Jonathan L Haines  7 , Angela L Jefferson  1 , Walter A Kukull  16 , C Dirk Keene  17 , Andrew J Saykin  18   19   20 , Paul M Thompson  21 , Eden R Martin  8 , Marilyn S Albert  22 , Sterling C Johnson  23 , Corinne D Engelman  23   24 , Luigi Ferrucci  25 , David A Bennett  26 , Lisa L Barnes  26 , Julie A Schneider  26 , Reisa A Sperling  27 , Susan M Resnick  13 , Paul K Crane  3 , Logan Dumitrescu  1   2 , Timothy J Hohman  28   29
Collaborators, Affiliations
Free article

Genetic modifiers of APOE-ε4-associated cognitive decline

Alex G Contreras et al. Nat Commun. .
Free article

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.

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Conflict of interest statement

Competing interests: T.J.H., PhD, is a member of the scientific advisory board for Circular Genomics, serves as the deputy editor of Alzheimer’s & Dementia: Translational Research and Clinical Intervention, and serves as Section Editor for Alzheimer’s & Dementia. P.M.T., PhD, received partial grant support from Biogen, Inc., for research unrelated to this work. S.J. has served on advisory boards for AlzPath and Enigma Biomedical in the past 3 years. The remaining authors declare no competing interests.

References

    1. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/dementia.
    1. Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Primer 7, 1–21 (2021).
    1. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).
    1. Liu, C.-C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013).
    1. Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 54, 412–436 (2022).

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