Genetic Modifiers of <scp>ABCA1</scp> Activity Interact with <scp> <i>APOE</i> </scp> Isoforms to Mediate Alzheimer's Disease Risk

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: Genetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026.

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Journal
Annals of Neurology
Published
2026-08-03
DOI
https://doi.org/10.1002/ana.78303
Primary Topic
Cholesterol and Lipid Metabolism
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article

Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk

Yann Le Guen, Camille Charbonnier, Ricardo Hernández Arriaza, Marc Hulsman et al.
Annals of Neurology
Cholesterol and Lipid Metabolism
article

Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk

Yann Le Guen, Camille Charbonnier, Ricardo Hernández Arriaza, Marc Hulsman, Chaitan Khosla, Manon Muntaner, Céline Bellenguez, Michael D. Greicius, Simon Mead, Andrés Peña‐Tauber, Benjamin Grenier‐Boley, Julie Willams, Dylan Reil, Orio Dols-Icardo, John van Swieten, John Hardy, Michael Wagner, Rebecca Sims, Jean‐François Deleuze, Philippe Amouyel, Gaël Nicolas, Alfredo Ramirez, Henne Holstege, Junyoung Park, Jean‐Charles Lambert
article en

Abstract

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. INTERPRETATION: Genetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026.

Annals of Neurology
Inserm (FR), Université de Lille (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), University Hospital Bonn (DE), Institut Pasteur de Lille (FR), German Center for Neurodegenerative Diseases (DE), Hospital de Sant Pau (ES), Erasmus MC (NL), Centre Hospitalier Universitaire de Lille (FR), Centre National de Recherche en Génomique Humaine (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Normandie Université (FR), Amsterdam Neuroscience (NL), Institute for Neurodegenerative Disorders (US), Dementia UK (GB), UK Dementia Research Institute (GB), MRC Prion Unit (GB), Stanford Medicine (US), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), University Hospital Cologne (DE), Centre Hospitalier Universitaire de Rouen (FR), University College London (GB), Université de Rouen Normandie (FR), Cardiff University (GB), Vrije Universiteit Amsterdam (NL), Erasmus University Rotterdam (NL), Stanford University (US), Delft University of Technology (NL)
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Cholesterol and Lipid Metabolism
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