Genetic Modifiers of
ABCA1
Activity Interact with
APOE
Isoforms to Mediate Alzheimer's Disease Ri
Andrés Peña‐Tauber, Ricardo Hernández Arriaza, Dylan Reil, Manon Muntaner, Junyoung Park, Benjamin Grenier‐Boley, Marc Hulsman, Philippe Amouyel, Céline Bellenguez, Camille Charbonnier, Jean‐François Deleuze, Orio Dols‐Icardo, John Hardy, Henne Holstege, Gaël Nicolas, Simon Mead, Michael Wagner, Alfredo Ramirez, Rebecca Sims, John van Swieten, Julie Willams, Jean‐Charles Lambert, Chaitan Khosla, Yann Le Guen, Michael D Greicius 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 ε 2 and ε 4 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 ε 2 and ε 4. Predicted ABCA1 activity based on HDL‐associated variants was associated with reduced AD risk and interacted with APOE ε 4. 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