APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers’s disease

Qvist Thomassen, Jesper, Leonard, Hampton, Ulms, Brittany, Grenier-Boley, Benjamin, Heikkinen, Sami, Castillo Morales, Atahualpa, Williams, Julie ORCID: https://orcid.org/0000-0002-4069-0259, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Holmans, Peter A. ORCID: https://orcid.org/0000-0003-0870-9412 and Sims, Rebecca ORCID: https://orcid.org/0000-0002-3885-1199 2026. APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers’s disease. Nature Genetics 10.1038/s41588-026-02713-9

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Abstract

Among the more than 90 identified genetic risk loci for late-onset Alzheimer’s disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1,2,3,4,5,6,7,8,9,10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11,12,13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	Full author list available at DOI
Publisher:	Nature Research
ISSN:	1061-4036
Date of First Compliant Deposit:	22 September 2026
Date of Acceptance:	14 July 2026
Last Modified:	22 Sep 2026 09:27
URI:	https://orca.cardiff.ac.uk/id/eprint/189754

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