{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:47:05Z","timestamp":1790272025076,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011631","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000}}],"reference-count":74,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG064614"],"award-info":[{"award-number":["R01AG064614"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01AG079850"],"award-info":[{"award-number":["U01AG079850"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30AG066462"],"award-info":[{"award-number":["P30AG066462"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01AG003991"],"award-info":[{"award-number":["P01AG003991"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01AG032984"],"award-info":[{"award-number":["U01AG032984"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54AG052427"],"award-info":[{"award-number":["U54AG052427"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    The genetic component of early-onset Alzheimer disease (EOAD), accounting for ~10% of all Alzheimer\u2019s disease (AD) cases, is largely unexplained. Recent studies suggest that EOAD may be enriched for variants acting in the lipid pathway. The current study examines the shared genetic heritability between EOAD and the lipid pathway using genome-wide multi-trait genetic covariance analyses. Summary statistics were obtained from the GWAS meta-analyses of EOAD by the Alzheimer\u2019s Disease Genetics Consortium (\n                    <jats:italic>n<\/jats:italic>\n                    =19,668) and five blood lipid traits by the Global Lipids Genetics Consortium (\n                    <jats:italic>n<\/jats:italic>\n                    =1,320,016). The significant results were compared between the EOAD and lipids GWAS and genetic covariance analyses were performed via SUPERGNOVA. Genes in linkage disequilibrium (LD) with top EOAD hits in identified regions of covariance with lipid traits were scored and ranked for causality by combining evidence from gene-based analysis, AD-risk scores incorporating transcriptomic and proteomic evidence, eQTL data, eQTL colocalization analyses, DNA methylation data, and single-cell RNA sequencing analyses. Direct comparison of GWAS results showed 5 loci overlapping between EOAD and at least one lipid trait harboring\n                    <jats:italic>APOE<\/jats:italic>\n                    ,\n                    <jats:italic>TREM2<\/jats:italic>\n                    ,\n                    <jats:italic>MS4A4E<\/jats:italic>\n                    ,\n                    <jats:italic>LILRA5<\/jats:italic>\n                    , and\n                    <jats:italic>LRRC25<\/jats:italic>\n                    . Local genetic covariance analyses identified 3 regions of covariance between EOAD and at least one lipid trait. Gene prioritization nominated 3 likely causative genes at these loci:\n                    <jats:italic>ANKDD1B<\/jats:italic>\n                    ,\n                    <jats:italic>CUZD1<\/jats:italic>\n                    , and\n                    <jats:italic>MS4A64<\/jats:italic>\n                    .The current study identified genetic covariance between EOAD and lipids, providing further evidence of shared genetic architecture and mechanistic pathways between the two traits.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011631","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T13:31:01Z","timestamp":1742218261000},"page":"e1011631","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Local genetic covariance analysis with lipid traits identifies novel loci for early-onset Alzheimer\u2019s Disease"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4931-3239","authenticated-orcid":true,"given":"Nicholas R.","family":"Ray","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0217-4808","authenticated-orcid":true,"given":"Joseph","family":"Bradley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7045-5068","authenticated-orcid":true,"given":"Elanur","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8164-9762","authenticated-orcid":true,"given":"Caghan","family":"Kizil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiji T.","family":"Kurup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eden R.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6382-9428","authenticated-orcid":true,"given":"Hans-Ulrich","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9515-5157","authenticated-orcid":true,"given":"Brian W.","family":"Kunkle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":true,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Alzheimer\u2019s Disease Genetics Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary W.","family":"Beecham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-2899","authenticated-orcid":true,"given":"Carlos","family":"Cruchaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8757-7889","authenticated-orcid":true,"given":"Christiane","family":"Reitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"issue":"2","key":"pgen.1011631.ref001","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1177\/1533317509352335","article-title":"The plight of caring for young patients with frontotemporal dementia","volume":"25","author":"Z Chemali","year":"2010","journal-title":"Am J Alzheimers Dis Other Demen"},{"issue":"4","key":"pgen.1011631.ref002","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1111\/ene.12325","article-title":"Estimating the burden of early onset dementia; 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