Journal Article

DZNE-2026-00981

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk.

Peña-Tauber, A. ; Hernández Arriaza, R. ; Reil, D. ; Muntaner, M. ; Park, J. ; Grenier-Boley, B. ; Hulsman, M. ; Amouyel, P. ; Bellenguez, C. ; Charbonnier, C. ; Deleuze, J.-F. ; Dols-Icardo, O. ; Hardy, J. ; Holstege, H. ; Nicolas, G. ; Mead, S. ; Wagner, M.DZNE* ; Ramirez, A.DZNE* ; Sims, R. ; van Swieten, J. ; Willams, J. ; Lambert, J.-C. ; Khosla, C. ; Le Guen, Y. ; Greicius, M. D.

2026
Wiley-Blackwell Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/ana.78303

Abstract: ATP-binding cassette transporter A1 (ABCA1) has been associated with Alzheimer's disease (AD), but the mechanisms by which it impacts disease risk are unknown. ABCA1 is known to bind apolipoprotein E (ApoE) and catalyze apolipoprotein lipidation. We explored whether genetic variants altering ABCA1 function interact with APOE isoforms to modify AD risk.Using data from the Alzheimer's Disease Sequencing Project (ADSP), UK Biobank, and the Alzheimer Disease European Sequencing consortium, we assessed the impact of ABCA1 variants on AD risk in APOE subgroups and tested for statistical interactions with APOE ε2 and ε4 in an all-APOE cohort. We first examined damaging nonsynonymous ABCA1 variants previously associated with AD. We then constructed a measure of predicted ABCA1 activity based on HDL-associated variants and tested its association with AD risk. Finally, we explored potential pathogenic mechanisms of missense variants of interest.Damaging nonsynonymous ABCA1 variants had differential AD risk effects between APOE genotype groups and exhibited interaction effects with APOE ε2 and ε4. Predicted ABCA1 activity based on HDL-associated variants was associated with reduced AD risk and interacted with APOE ε4. Replication analyses suggested similar differences in effect size of ABCA1 variants between APOE groups and had concordant effect directions, although not statistically significant, in the APOE interaction model. ABCA1 missense variants N1800H and E1172D were strongly associated with plasma HDL and interacted with APOE in AD risk. In cell-based assays, ABCA1-N1800H showed plasma membrane localization defects potentially driven by misfolding.Genetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026;100:737-750.

Keyword(s): Humans (MeSH) ; ATP Binding Cassette Transporter 1: genetics (MeSH) ; ATP Binding Cassette Transporter 1: metabolism (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Protein Isoforms: genetics (MeSH) ; Apolipoproteins E: genetics (MeSH) ; Genetic Predisposition to Disease: genetics (MeSH) ; Female (MeSH) ; Apolipoprotein E4: genetics (MeSH) ; Male (MeSH) ; ATP Binding Cassette Transporter 1 ; ABCA1 protein, human ; Protein Isoforms ; Apolipoproteins E ; Apolipoprotein E4

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Contributing Institute(s):

1. Neuropsychology (AG Wagner)
2. Patient Studies (Bonn) (Patient Studies (Bonn))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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