{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T11:45:16Z","timestamp":1769514316654,"version":"3.49.0"},"posted":{"date-parts":[[2025,3,13]]},"group-title":"Neurology","reference-count":15,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T00:00:00Z","timestamp":1741824000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,13]]},"abstract":"Abstract<\/jats:title>\n \n The\n Apolipoprotein E (APOE)<\/jats:italic>\n e4 and e2 alleles are respectively the most risk increasing and risk decreasing, common genetic risk factors for Alzheimer\u2019s disease (AD)\n 1,2<\/jats:sup>\n . They strongly affect A\u03b2 burden in the brain parenchyma\n 1<\/jats:sup>\n , a core hallmark of AD, but also at the level of the brain vasculature, i.e. cerebral amyloid angiopathy (CAA)\n 1,3<\/jats:sup>\n , which in turn relates to increased risk for amyloid-related imaging abnormalities (ARIA) in\n APOE<\/jats:italic>\n *4 carriers when receiving anti-A\u03b2 antibody treatments\n 4<\/jats:sup>\n . This makes\n APOE<\/jats:italic>\n a highly pursued AD drug target. A crucial question in the field is whether it would be beneficial to either increase or decrease\n APOE<\/jats:italic>\n (particularly\n APOE<\/jats:italic>\n *4) levels\n 5<\/jats:sup>\n . The answer from rodent work appears to converge on \u201cdecreasing\n APOE<\/jats:italic>\n levels\u201d\n 5\u20137<\/jats:sup>\n , with initial human studies supporting this\n 5,8,9<\/jats:sup>\n . 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\n APOE<\/jats:italic>\n locus independent of\n APOE<\/jats:italic>\n *4 and\n APOE<\/jats:italic>\n *2 genotypes\n 10<\/jats:sup>\n . Downstream analyses suggested this signal links to the nearby\n APOC2<\/jats:italic>\n 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\n APOE<\/jats:italic>\n expression, which would importantly support the evidence in favor of \u201cdecreasing\n APOE<\/jats:italic>\n levels\u201d and further herald this promising therapeutic avenue, not just for AD, but also for CAA. We additionally provide complimentary results regarding this locus\u2019 association with CAA and AD risk from analyses that we conducted parallel to Shade et al. 2024.\n <\/jats:p>","DOI":"10.1101\/2025.03.10.25323519","type":"posted-content","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T16:05:19Z","timestamp":1741881919000},"source":"Crossref","is-referenced-by-count":1,"title":["A Quantitative Trait Locus for Reduced Microglial\n APOE<\/i>\n Expression Associates with Reduced Cerebral Amyloid Angiopathy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7748-9033","authenticated-orcid":false,"given":"Michael E.","family":"Belloy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Graff-Radford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Greicius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025032002492539000_2025.03.10.25323519v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.01.056"},{"key":"2025032002492539000_2025.03.10.25323519v1.2","doi-asserted-by":"publisher","DOI":"10.1001\/JAMANEUROL.2023.3599"},{"key":"2025032002492539000_2025.03.10.25323519v1.3","doi-asserted-by":"crossref","unstructured":"Reddy, J. S. et al. Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer\u2019s disease. Acta Neuropathol Commun 9, (2021).","DOI":"10.1186\/s40478-021-01199-2"},{"key":"2025032002492539000_2025.03.10.25323519v1.4","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.5205"},{"key":"2025032002492539000_2025.03.10.25323519v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26864"},{"key":"2025032002492539000_2025.03.10.25323519v1.6","doi-asserted-by":"crossref","unstructured":"Xiong, M. et al. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci Transl Med 13, (2021).","DOI":"10.1126\/scitranslmed.abd7522"},{"key":"2025032002492539000_2025.03.10.25323519v1.7","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/ana.26351","article-title":"APOE Antibody Inhibits A\u03b2-Associated Tau Seeding and Spreading in a Mouse Model","volume":"91","year":"2022","journal-title":"Ann Neurol"},{"key":"2025032002492539000_2025.03.10.25323519v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2024.01.008"},{"key":"2025032002492539000_2025.03.10.25323519v1.9","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1001\/jamaneurol.2014.2011","article-title":"Eiects of the absence of apolipoprotein E on lipoproteins, neurocognitive function, and retinal function","volume":"71","year":"2014","journal-title":"JAMA Neurol"},{"key":"2025032002492539000_2025.03.10.25323519v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01939-9"},{"key":"2025032002492539000_2025.03.10.25323519v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01685-y"},{"key":"2025032002492539000_2025.03.10.25323519v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01149-1"},{"key":"2025032002492539000_2025.03.10.25323519v1.13","doi-asserted-by":"crossref","unstructured":"Belloy, M. E. et al. Challenges at the APOE locus: A robust quality control approach for accurate APOE genotyping. Alzheimers Res Ther 14, (2022).","DOI":"10.1186\/s13195-022-00962-4"},{"key":"2025032002492539000_2025.03.10.25323519v1.14","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2024.2843"},{"key":"2025032002492539000_2025.03.10.25323519v1.15","doi-asserted-by":"publisher","DOI":"10.1159\/000115751"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.03.10.25323519","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:30:28Z","timestamp":1768509028000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.03.10.25323519"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,13]]},"references-count":15,"URL":"https:\/\/doi.org\/10.1101\/2025.03.10.25323519","relation":{},"subject":[],"published":{"date-parts":[[2025,3,13]]},"subtype":"preprint"}}