ABCA1 activity is associated with reduced Alzheimer’s Disease risk in APOE ε4 non-carriers

Background and Objectives ABCA1 has been associated with Alzheimer’s Disease (AD) via large-scale genetic studies, but the mechanisms by which it impacts disease risk are unknown. ABCA1 catalyzes apolipoprotein lipidation in the central nervous system and is known to interact molecularly with ApoE. We explored whether variants altering ABCA1 activity depend on the presence of different APOE isoforms to modify AD risk. Methods We meta-analyzed European- and African-ancestry whole-genome and whole-exome sequencing datasets from the Alzheimer’s Disease Sequencing Project and UK Biobank. We used Cox hazards regression to assess the impact of rare (MAF < 1%) predicted damaging (loss-of-function, or missense with a REVEL score > 0.75) variants in ABCA1 on AD risk in APOE subgroups and performed APOE interaction analyses considering all APOE genotypes. We then leveraged plasma HDL levels, a phenotype known to be impacted by ABCA1 variants, as a measure of ABCA1 activity and examined whether cumulative effects on HDL levels by ABCA1 missense variants predict AD risk. Results Rare damaging (LOF + REVEL ≥ 75) variants on ABCA1 increased AD risk in APOE ε2/ε3 and ε3/ε3 but not ε3/ε4 or ε4/ε4 cohorts. Interaction analyses indicated that damaging ABCA1 variants increase AD risk considering all APOE isoforms (hazard ratio [HR] = 1.48; 95% confidence interval [CI] = 1.22, 1.79; p = 5.80E-05) and interact with both APOE ε2 (HR = 1.99; 95% CI = 1.30, 3.05; p = 0.002) and ε4 (HR = 0.76; 95% CI = 0.61, 0.95; p = 0.014). Predicted ABCA1 activity based on a weighted sum of HDL-associated ABCA1 missense variants was protective against AD (HR = 0.10; 95% CI = 0.04, 0.27; p = 2.83E-06) and interacted with APOE ε4 to counteract this protective effect (HR = 11.66; 95% CI = 3.81, 35.66; p = 1.67E-05), while there was no significant interaction with ε2. Conclusions ABCA1 activity is protective against AD risk in APOE ε4 non-carriers. Distinct interactions between ABCA1 and the main APOE isoforms suggest the proteins may work together to affect AD risk and motivates the development and testing of ABCA1 therapeutics in specific APOE subpopulations.