A Quantitative Trait Locus for Reduced Microglial APOE Expression Associates with Reduced Cerebral Amyloid Angiopathy

Abstract The Apolipoprotein E (APOE) e4 and e2 alleles are respectively the most risk increasing and risk decreasing, common genetic risk factors for Alzheimer’s disease (AD) 1,2 . They strongly affect Aβ burden in the brain parenchyma 1 , a core hallmark of AD, but also at the level of the brain vasculature, i.e. cerebral amyloid angiopathy (CAA) 1,3 , which in turn relates to increased risk for amyloid-related imaging abnormalities (ARIA) in APOE *4 carriers when receiving anti-Aβ antibody treatments 4 . This makes APOE a highly pursued AD drug target. A crucial question in the field is whether it would be beneficial to either increase or decrease APOE (particularly APOE *4) levels 5 . The answer from rodent work appears to converge on “decreasing APOE levels” 5–7 , with initial human studies supporting this 5,8,9 . Human genetic evidence however remains scarce and new insights are crucially needed to support clinical translation. Shade et al. 2024 conducted the largest to date genome-wide association study (GWAS) of various neuropathological traits, identifying a variant protective of CAA in the APOE locus independent of APOE *4 and APOE *2 genotypes 10 . Downstream analyses suggested this signal links to the nearby APOC2 gene through local effects on methylation. We applaud the authors on their timely, relevant, and well-conducted study. Here, we extend on these findings, highlighting there is compelling evidence that their genetic signal for reduced CAA relates to an effect on reduced microglial APOE expression, which would importantly support the evidence in favor of “decreasing APOE levels” and further herald this promising therapeutic avenue, not just for AD, but also for CAA. We additionally provide complimentary results regarding this locus’ association with CAA and AD risk from analyses that we conducted parallel to Shade et al. 2024.