{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T06:12:47Z","timestamp":1778739167010,"version":"3.51.4"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Public Health"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Circulating polyunsaturated fatty acids (PUFAs) have been implicated in neurodegenerative processes, yet epidemiological evidence remains inconsistent. Genetic susceptibility to Alzheimer's disease (AD), commonly indexed by a polygenic risk score (PRS), is a major determinant of dementia risk. However, few large-scale prospective studies have jointly examined plasma fatty acid profiles and genetic liability to AD in relation to incident dementia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To investigate the independent and combined associations of plasma omega-3 PUFAs, omega-6 PUFAs, and the omega-6\/omega-3 ratio with incident dementia, and to determine whether these associations vary according to AD-PRS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed data from 81,827 UK Biobank participants with baseline nuclear magnetic resonance (NMR) metabolomics and genetic information. Plasma fatty acids were quantified using standardized NMR spectroscopy, and genetic risk for AD was assessed using the Enhanced AD-PRS. Incident dementia was identified through linked hospital admission and death registry records. Multivariable-adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models. Dose\u2013response relationships and both additive and multiplicative interactions with AD-PRS were evaluated, alongside subgroup and sensitivity analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Over a median follow-up of 12.1 years, 1,335 participants developed dementia. Higher plasma omega-6 concentrations were consistently associated with a lower risk of dementia, corresponding to an approximately 15% risk reduction per 1 mmol\/L increase (HR 0.85, 95% CI 0.79\u20130.93,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.001). In contrast, plasma omega-3 levels (HR 0.97, 95% CI 0.77\u20131.23,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.81) and the omega-6\/omega-3 ratio (HR 0.96, 95% CI 0.85\u20131.09,\n                      <jats:italic>P<\/jats:italic>\n                      = 0.55) were not significantly associated with dementia risk. AD-PRS was a strong predictor of incident dementia; however, no statistically significant interactions were observed between AD-PRS and any fatty acid biomarker. Joint analyses suggested only modest attenuation of absolute genetic risk at higher omega-6 concentrations. Findings were robust across multiple sensitivity analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Higher plasma omega-6 PUFA levels were independently associated with a clinically meaningful reduction in dementia risk, whereas omega-3 PUFAs and the omega-6\/omega-3 ratio were not. Although elevated omega-6 modestly reduced absolute risk among individuals with high genetic susceptibility to AD, no meaningful gene\u2013nutrient interaction was detected. Further mechanistic and interventional studies are warranted to elucidate underlying pathways.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpubh.2026.1816467","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T05:33:43Z","timestamp":1778736823000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Higher plasma omega-6 fatty acids are associated with lower dementia risk: evidence from NMR metabolomics and Alzheimer's disease polygenic risk in the UK Biobank"],"prefix":"10.3389","volume":"14","author":[{"given":"Li","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, West China Second University Hospital","place":["Sichuan University, Chengdu, China"]},{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyin","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education","place":["Chengdu, China"]},{"name":"Department of Ultrasonic Medicine, West China Second University Hospital of Sichuan University","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, West China Second University Hospital","place":["Sichuan University, Chengdu, China"]},{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education","place":["Chengdu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/S1474-4422(21)00252-0","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the global burden of disease study 2019","volume":"20","year":"2021","journal-title":"Lancet Neurol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/S1474-4422(18)30499-X","article-title":"Global, Regional, and National Burden of Neurological Disorders, 1990-2016: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"18","year":"2019","journal-title":"Lancet Neurol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"71","DOI":"10.3390\/molecules30010071","article-title":"Molecular mechanisms linking omega-3 fatty acids and the gut-brain axis","volume":"30","author":"Zinkow","year":"2024","journal-title":"Molecules."},{"key":"B4","doi-asserted-by":"publisher","first-page":"12343","DOI":"10.1073\/pnas.1817557115","article-title":"ACSL6 is critical for maintaining brain DHA levels","volume":"115","author":"Chouinard-Watkins","year":"2018"},{"key":"B5","doi-asserted-by":"publisher","first-page":"102366","DOI":"10.1016\/j.plefa.2021.102366","article-title":"Linoleic acid and the regulation of glucose homeostasis: a review of the evidence","volume":"175","author":"Hamilton","year":"2021","journal-title":"Prostaglandins Leukot Essent Fatty Acids."},{"key":"B6","doi-asserted-by":"publisher","first-page":"986","DOI":"10.3390\/nu13030986","article-title":"Docosahexaenoic and arachidonic acids as neuroprotective nutrients throughout the life cycle","volume":"13","author":"Sambra","year":"2021","journal-title":"Nutrients."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.1016\/j.ajcnut.2023.04.001","article-title":"Alzheimer's Disease Neuroimaging Initiative; Xu W. 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