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Red blood cell (RBC) status of DHA is an objective measure of long-term dietary DHA intake. In this prospective observational study conducted within the Framingham Offspring Cohort (1490 dementia-free participants aged \u226565 years old), we examined the association of RBC DHA with incident AD, testing for an interaction with APOE-\u03b54 carriership. During the follow-up (median, 7.2 years), 131 cases of AD were documented. In fully adjusted models, risk for incident AD in the highest RBC DHA quintile (Q5) was 49% lower compared with the lowest quintile (Q1) (Hazard ratio [HR]: 0.51, 95% confidence interval [CI]: 0.27, 0.96). An increase in RBC DHA from Q1 to Q5 was predicted to provide an estimated 4.7 additional years of life free of AD. We observed an interaction DHA \u00d7 APOE-\u03b54 carriership for AD. Borderline statistical significance for a lower risk of AD was observed per standard deviation increase in RBC DHA (HR: 0.71, 95% CI: 0.51, 1.00, p = 0.053) in APOE-\u03b54 carriers, but not in non-carriers (HR: 0.85, 95% CI: 0.65, 1.11, p = 0.240). These findings add to the increasing body of literature suggesting a robust association worth exploring dietary DHA as one strategy to prevent or delay AD.<\/jats:p>","DOI":"10.3390\/nu14122408","type":"journal-article","created":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T23:55:24Z","timestamp":1655078124000},"page":"2408","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Red Blood Cell DHA Is Inversely Associated with Risk of Incident Alzheimer\u2019s Disease and All-Cause Dementia: Framingham Offspring Study"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5038-2794","authenticated-orcid":false,"given":"Aleix","family":"Sala-Vila","sequence":"first","affiliation":[{"name":"Fatty Acid Research Institute, Sioux Falls, SD 57106, USA"},{"name":"Cardiovascular Risk and Nutrition, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia L.","family":"Satizabal","sequence":"additional","affiliation":[{"name":"Glenn Biggs Institute for Alzheimer\u2019s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX 78299, USA"},{"name":"Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX 78229, USA"},{"name":"The Framingham Heart Study, Framingham, MA 01702, USA"},{"name":"Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Tintle","sequence":"additional","affiliation":[{"name":"Fatty Acid Research Institute, Sioux Falls, SD 57106, USA"},{"name":"Department of Statistics, Dordt University, Sioux Center, IA 51250, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7392-9289","authenticated-orcid":false,"given":"Debora","family":"Melo van Lent","sequence":"additional","affiliation":[{"name":"Glenn Biggs Institute for Alzheimer\u2019s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX 78299, USA"},{"name":"Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX 78229, USA"},{"name":"The Framingham Heart Study, Framingham, MA 01702, USA"},{"name":"Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramachandran S.","family":"Vasan","sequence":"additional","affiliation":[{"name":"Schools of Medicine and Epidemiology, Boston University, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa S.","family":"Beiser","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudha","family":"Seshadri","sequence":"additional","affiliation":[{"name":"Glenn Biggs Institute for Alzheimer\u2019s and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX 78299, USA"},{"name":"Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX 78229, USA"},{"name":"The Framingham Heart Study, Framingham, MA 01702, USA"},{"name":"Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3042-9353","authenticated-orcid":false,"given":"William S.","family":"Harris","sequence":"additional","affiliation":[{"name":"Fatty Acid Research Institute, Sioux Falls, SD 57106, USA"},{"name":"Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57069, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1093\/advances\/nmaa053","article-title":"Dietary Factors and Neurodegenerative Disorders: An Umbrella Review of Meta-Analyses of Prospective Studies","volume":"11","author":"Barbaresko","year":"2020","journal-title":"Adv. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"52","DOI":"10.3389\/fnagi.2015.00052","article-title":"Long-chain omega-3 fatty acids and the brain: A review of the independent and shared effects of EPA, DPA and DHA","volume":"7","author":"Dyall","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.nbd.2015.09.002","article-title":"Dietary DHA supplementation in an APP\/PS1 transgenic rat model of AD reduces behavioral and A\u03b2 pathology and modulates A\u03b2 oligomerization","volume":"82","author":"Teng","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Pifferi, F., Cunnane, S.C., and Guesnet, P. (2020). Evidence of the Role of Omega-3 Polyunsaturated Fatty Acids in Brain Glucose Metabolism. Nutrients, 12.","DOI":"10.3390\/nu12051382"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"905","DOI":"10.3945\/an.116.012187","article-title":"Omega-3 Polyunsaturated Fatty Acids and Oxylipins in Neuroinflammation and Management of Alzheimer Disease","volume":"7","author":"Devassy","year":"2016","journal-title":"Adv. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1001\/jamaneurol.2016.4899","article-title":"Association of Docosahexaenoic Acid Supplementation with Alzheimer Disease Stage in Apolipoprotein E \u03b54 Carriers: A Review","volume":"74","author":"Yassine","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.plipres.2008.03.003","article-title":"Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake","volume":"47","author":"Hodson","year":"2008","journal-title":"Prog. Lipid Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.clinbiochem.2009.08.016","article-title":"Biological variability of blood omega-3 biomarkers","volume":"43","author":"Harris","year":"2010","journal-title":"Clin. Biochem."},{"key":"ref_9","first-page":"78","article-title":"The Relationship of Omega 3 Polyunsaturated Fatty Acids in Red Blood Cell Membranes with Cognitive Function and Brain Structure: A Review Focussed on Alzheimer\u2019s Disease","volume":"5","author":"Hooper","year":"2018","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"101300","DOI":"10.1016\/j.arr.2021.101300","article-title":"Associations of Omega-3 fatty acids with brain morphology and volume in cognitively healthy older adults: A narrative review","volume":"67","author":"Macaron","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"184","DOI":"10.3945\/ajcn.2008.26987","article-title":"Omega-3 fatty acids and risk of dementia: The Canadian Study of Health and Aging","volume":"90","author":"Verreault","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.plefa.2017.06.006","article-title":"Erythrocyte omega-3 fatty acids are inversely associated with incident dementia: Secondary analyses of longitudinal data from the Women\u2019s Health Initiative Memory Study (WHIMS)","volume":"121","author":"Ammann","year":"2017","journal-title":"Prostaglandins Leukot. Essent. Fatty Acids"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1001\/archneur.63.11.1545","article-title":"Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: The Framingham Heart Study","volume":"63","author":"Schaefer","year":"2006","journal-title":"Arch. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s12603-011-0009-5","article-title":"High dietary and plasma levels of the omega-3 fatty acid docosahexaenoic acid are associated with decreased dementia risk: The Rancho Bernardo study","volume":"15","author":"Lopez","year":"2011","journal-title":"J. Nutr. Health Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1002\/alz.12195","article-title":"Blood polyunsaturated omega-3 fatty acids, brain atrophy, cognitive decline, and dementia risk","volume":"17","author":"Thomas","year":"2021","journal-title":"Alzheimers Dement."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.jalz.2017.11.012","article-title":"Circulating metabolites and general cognitive ability and dementia: Evidence from 11 cohort studies","volume":"14","author":"Teunissen","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1093\/ajcn\/88.3.714","article-title":"Low plasma eicosapentaenoic acid and depressive symptomatology are independent predictors of dementia risk","volume":"88","author":"Samieri","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Melo van Lent, D., Egert, S., Wolfsgruber, S., Kleineidam, L., Weinhold, L., Wagner-Thelen, H., Maier, W., Jessen, F., Ramirez, A., and Schmid, M. (2021). Eicosapentaenoic Acid Is Associated with Decreased Incidence of Alzheimer\u2019s Dementia in the Oldest Old. Nutrients, 13.","DOI":"10.3390\/nu13020461"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2105\/AJPH.41.3.279","article-title":"Epidemiological approaches to heart disease: The Framingham Study","volume":"41","author":"Dawber","year":"1951","journal-title":"Am. J. Public Health Nations Health"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/0091-7435(75)90037-7","article-title":"The Framingham Offspring Study. Design and preliminary data","volume":"4","author":"Feinleib","year":"1975","journal-title":"Prev. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S0022-2275(20)43176-1","article-title":"Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI","volume":"31","author":"Hixson","year":"1990","journal-title":"J. Lipid Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.3945\/jn.112.158295","article-title":"Changes in erythrocyte membrane trans and marine fatty acids between 1999 and 2006 in older Americans","volume":"142","author":"Harris","year":"2012","journal-title":"J. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1212\/WNL.42.1.115","article-title":"Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study","volume":"42","author":"Bachman","year":"1992","journal-title":"Neurology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1212\/WNL.34.7.939","article-title":"Clinical diagnosis of Alzheimer\u2019s disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer\u2019s Disease","volume":"34","author":"McKhann","year":"1984","journal-title":"Neurology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1161\/CIR.0000000000000574","article-title":"Seafood Long-Chain n-3 Polyunsaturated Fatty Acids and Cardiovascular Disease: A Science Advisory from the American Heart Association","volume":"138","author":"Rimm","year":"2018","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"(2022). 2022 Alzheimer\u2019s disease facts and figures. Alzheimers Dement., 18, 700\u2013789.","DOI":"10.1002\/alz.12638"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1515\/fhep-2014-0013","article-title":"The Value of Delaying Alzheimer\u2019s Disease Onset","volume":"18","author":"Zissimopoulos","year":"2014","journal-title":"Forum. Health Econ. Policy"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1212\/WNL.0b013e318249f6a9","article-title":"Red blood cell \u03c9-3 fatty acid levels and markers of accelerated brain aging","volume":"78","author":"Tan","year":"2012","journal-title":"Neurology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2273","DOI":"10.1002\/brb3.2273","article-title":"Omega-3 fatty acids are associated with blood-brain barrier integrity in a healthy aging population","volume":"11","author":"Barnes","year":"2021","journal-title":"Brain Behav."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1001\/jamaneurol.2016.1924","article-title":"Association of Serum Docosahexaenoic Acid with Cerebral Amyloidosis","volume":"73","author":"Yassine","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.3945\/ajcn.2009.29121","article-title":"Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: A randomized, double-blind, controlled trial","volume":"91","author":"Dangour","year":"2010","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1001\/jama.2015.9677","article-title":"Effect of Omega-3 Fatty Acids, Lutein\/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial","volume":"314","author":"Chew","year":"2015","journal-title":"JAMA"},{"key":"ref_33","first-page":"e12288","article-title":"Marine n-3 fatty acids and cognitive change among older adults in the VITAL randomized trial","volume":"8","author":"Kang","year":"2022","journal-title":"Alzheimers Dement."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S1474-4422(17)30040-6","article-title":"Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): A randomised, placebo-controlled trial","volume":"16","author":"Andrieu","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.bbi.2021.10.014","article-title":"Omega-3 fatty acids and blood-based biomarkers in Alzheimer\u2019s disease and mild cognitive impairment: A randomized placebo-controlled trial","volume":"99","author":"Lin","year":"2022","journal-title":"Brain Behav. Immun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.plefa.2014.11.007","article-title":"A genome-wide association study of saturated, mono- and polyunsaturated red blood cell fatty acids in the Framingham Heart Offspring Study","volume":"94","author":"Tintle","year":"2015","journal-title":"Prostaglandins Leukot. Essent. Fatty Acids"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kalsbeek, A., Veenstra, J., Westra, J., Disselkoen, C., Koch, K., McKenzie, K.A., O\u2019Bott, J., Vander Woude, J., Fischer, K., and Shearer, G.C. (2018). A genome-wide association study of red-blood cell fatty acids and ratios incorporating dietary covariates: Framingham Heart Study Offspring Cohort. PLoS ONE., 13.","DOI":"10.1371\/journal.pone.0194882"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1007\/s12603-017-0957-5","article-title":"Cognitive Changes with Omega-3 Polyunsaturated Fatty Acids in Non-Demented Older Adults with Low Omega-3 Index","volume":"21","author":"Hooper","year":"2017","journal-title":"J. Nutr. Health Aging"},{"key":"ref_39","unstructured":"(2022, January 24). Prevention of Cognitive Decline in Older Adults with Low Dha\/Epa Index in Red Blood Cells (LO-MAPT), Available online: clinicaltrials.gov\/ct2\/show\/NCT03691519."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"102883","DOI":"10.1016\/j.ebiom.2020.102883","article-title":"Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial","volume":"59","author":"Arellanes","year":"2020","journal-title":"eBioMedicine"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/12\/2408\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:27:19Z","timestamp":1760138839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/12\/2408"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,9]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["nu14122408"],"URL":"https:\/\/doi.org\/10.3390\/nu14122408","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,9]]}}}