A Quantitative Trait Locus for Reduced MicroglialAPOEExpression 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 parenchyma1, 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 treatments4. 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) levels5. The answer from rodent work appears to converge on “decreasing APOE levels”5–7, with initial human studies supporting this5,8,9. 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 genotypes10. 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement Funding for this study was provided by the NIH (R00AG075238, M.E.B; AG060747 and AG047366, M.D.G; AG006786, J.G-R.) Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The current study protocol was granted an exemption by the Stanford Institutional Review Board because the analyses were carried out on de-identified, off-the-shelf data; therefore, additional informed consent was not required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes