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

Background and ObjectivesABCA1 has been associated with Alzheimers 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. MethodsWe meta-analyzed European- and African-ancestry whole-genome and whole-exome sequencing datasets from the Alzheimers 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. ResultsRare damaging (LOF + REVEL [&ge;] 75) variants on ABCA1 increased AD risk in APOE {varepsilon}2/{varepsilon}3 and {varepsilon}3/{varepsilon}3 but not {varepsilon}3/{varepsilon}4 or {varepsilon}4/{varepsilon}4 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 {varepsilon}2 (HR = 1.99; 95% CI = 1.30, 3.05; p = 0.002) and {varepsilon}4 (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 {varepsilon}4 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 {varepsilon}2. ConclusionsABCA1 activity is protective against AD risk in APOE {varepsilon}4 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.