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AT000162"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Apolipoprotein E (APOE) allele 4 (APOE4), one of the robust genetic risk factors for AD, has also been associated with cognitive decline in terms of memory, executive function, language, and global cognitive function. APOE genotype-stratified analysis can help to identify additional genetic loci which might be masked due to a strong effect of APOE4. We conducted a genome-wide meta-analysis in APOE2 carriers, APOE4 carriers, and APOE 3\/3 homozygote groups among 2969 non-Hispanic Whites aged \u2265 65 years using slopes of decline over time across five cognitive domains (attention, language, executive function, memory, and visuospatial function) and global cognitive function. We identified novel genome-wide significant associations for decline in global cognitive function in the intergenic region between RNU7-66P\/RNA5SP208 at rs116379916 (p = 1.44 \u00d7 10\u22129) in the APOE 3\/3 group and for decline in language in the intergenic region between LINC0221\/DTWD2 at rs13187183 (p = 3.79 \u00d7 10\u22128) in APOE4 carriers. A previously reported locus for decline in attention near RASEF at rs6559700 (p = 9.95 \u00d7 10\u22129) was found to be confined to the APOE 3\/3 group. We also found two sub-threshold significant associations in the APOE 2 group for decline in attention (IL1RL2\/rs77127114; p = 8.64 \u00d7 10\u22128) and decline in language (YTHDC2\/KCNN2, rs116191836; p = 5.66 \u00d7 10\u22128). Our study points to potential biological pathways pertaining to specific domains within each APOE genotype group, and the findings suggest that immune-related pathways, plasma levels of polysaturated fatty acids, and bitter taste receptors may play roles in cognitive decline. Our findings enhance the understanding of cognitive aging and provide a framework for future studies.<\/jats:p>","DOI":"10.3390\/ijms26146940","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T09:33:53Z","timestamp":1753090433000},"page":"6940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["APOE Genotype-Stratified Meta-Analysis of Cognitive Decline Reveals Novel Loci for Language and Global Cognitive Function in Older Adults"],"prefix":"10.3390","volume":"26","author":[{"given":"Vibha","family":"Acharya","sequence":"first","affiliation":[{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang-Hsien","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth E.","family":"Snitz","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Ganguli","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Department of Epidemiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven T.","family":"DeKosky","sequence":"additional","affiliation":[{"name":"McKnight Brain Institute and Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar L.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor","family":"Feingold","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Ilyas","family":"Kamboh","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1126\/science.1254403","article-title":"Human cognitive aging: Corriger la fortune?","volume":"346","author":"Lindenberger","year":"2014","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1126\/science.276.5318.1560","article-title":"Substantial Genetic Influence on Cognitive Abilities in Twins 80 or More Years Old","volume":"276","author":"Mcclearn","year":"1997","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s11065-015-9280-2","article-title":"A Meta-analysis of Heritability of Cognitive Aging: Minding the \u201cMissing Heritability\u201d Gap","volume":"25","author":"Reynolds","year":"2015","journal-title":"Neuropsychol. 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