{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:41:04Z","timestamp":1776919264113,"version":"3.51.2"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T00:00:00Z","timestamp":1776297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Mild cognitive impairment (MCI), the prodromal stage of Alzheimer\u2019s disease, may be influenced by nutritional status and genetic susceptibility. This systematic review synthesised evidence on how nutritional biomarkers interact with genetic variants, particularly APOE \u03b54, to influence cognitive outcomes in individuals with MCI. Methods: Following PRISMA 2020 guidelines, seven studies were included (three longitudinal, two randomised controlled trials, and two cross-sectional) involving adults aged \u226555 years with MCI. Nutritional exposures comprised plasma or serum concentrations of vitamins A, D, E, the vitamin B group, lipids, selenium, and ketogenic medium-chain triglycerides. Genetic risk was assessed primarily through APOE \u03b54 status. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence using GRADE. Due to heterogeneity in biomarkers, cognitive tools, and study designs, findings were synthesised narratively. Results: Across nutrient categories, higher concentrations of vitamin D, selenium, and antioxidants were associated with better cognitive outcomes. kMCT supplementation improved episodic memory and brain energy metabolism. Evidence for nutrient\u2013gene interactions was mixed: APOE \u03b54 modified responses to vitamin B group and selenium but showed limited influence on vitamin D, lipids, or kMCT effects. Heterogeneity in biomarker assays, cognitive tools, and genetic stratification limited comparability across studies. Conclusions: Nutritional biomarkers appear to influence cognitive trajectories in MCI, and some associations may differ by APOE \u03b54 status. However, small samples and limited genetic stratification constrain interpretation. Future research should prioritise standardised biomarker measurement, genetically stratified cohorts, and individual participant data meta-analyses to clarify nutrient\u2013gene interactions in MCI.<\/jats:p>","DOI":"10.3390\/nu18081263","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T14:05:36Z","timestamp":1776348336000},"page":"1263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interactions Between Blood Nutritional Biomarkers and Apolipoprotein E \u03b54 in the Progression of Mild Cognitive Impairment in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5443-8257","authenticated-orcid":false,"given":"Rasheedat","family":"Lawal","sequence":"first","affiliation":[{"name":"School of Sport, Nutrition and Allied Health Professions, Oxford Brookes University, Oxford OX3 0BP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5018-4184","authenticated-orcid":false,"given":"Sanjay","family":"Kumar","sequence":"additional","affiliation":[{"name":"School of Psychology, Social Work and Public Heath, Oxford Brookes University, Oxford OX3 0BP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4624-6706","authenticated-orcid":false,"given":"Rosemary","family":"Chigevenga","sequence":"additional","affiliation":[{"name":"School of Psychology, Social Work and Public Heath, Oxford Brookes University, Oxford OX3 0BP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0508-7507","authenticated-orcid":false,"given":"Shelly","family":"Coe","sequence":"additional","affiliation":[{"name":"School of Sport, Nutrition and Allied Health Professions, Oxford Brookes University, Oxford OX3 0BP, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"ref_1","unstructured":"Lira-De Le\u00f3n, K.I., Bertadillo-Jilote, A.D., Garc\u00eda-Guti\u00e9rrez, D.G., and Meraz-R\u00edos, M.A. (2020). Alzheimer\u2019s Disease and Type 2 Diabetes Mellitus: Molecular Mechanisms and Similarities. Neurodegenerative Diseases, IntechOpen. Chapter 4."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15132","DOI":"10.18632\/oncotarget.23738","article-title":"The genes associated with early-onset Alzheimer\u2019s disease","volume":"9","author":"Dai","year":"2018","journal-title":"Oncotarget"},{"key":"ref_3","unstructured":"Alzheimer\u2019s Research UK (2025, June 23). Prevalence and Incidence of Dementia. Available online: https:\/\/dementiastatistics.org\/about-dementia\/prevalence-and-incidence\/."},{"key":"ref_4","unstructured":"Alzheimer\u2019s Society (2025, June 23). Alzheimer\u2019s Society UK. Available online: https:\/\/www.alzheimers.org.uk\/."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.neurobiolaging.2010.03.025","article-title":"The genetic architecture of Alzheimer\u2019s disease: Beyond APP, PSENs and APOE","volume":"33","author":"Guerreiro","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.exger.2006.05.016","article-title":"Early detection of Alzheimer\u2019s disease using neuroimaging","volume":"42","author":"Mosconi","year":"2007","journal-title":"Exp. Gerontol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New insights into the genetic etiology of Alzheimer\u2019s disease and related dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.neurobiolaging.2020.04.024","article-title":"Age-dependent effect of APOE and polygenic component on Alzheimer\u2019s disease","volume":"93","author":"Bellou","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cummings, J.L., and Pillai, J.A. (2016). Neurodegenerative Diseases: Unifying Principles, Oxford University Press. Incorporated.","DOI":"10.1093\/med\/9780190233563.003.0001"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"102140","DOI":"10.1016\/j.genrep.2025.102140","article-title":"Relationship between plasma lipid and cognitive function in the elderly based on individual\u2019s diet and ApoE, CD36, SCARB1 genetic polymorphisms","volume":"38","author":"Ren","year":"2025","journal-title":"Gene Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Logue, M.W., Dasgupta, S., and Farrer, L.A. (2023). Genetics of Alzheimer\u2019s Disease in the African American Population. J. Clin. Med., 12.","DOI":"10.3390\/jcm12165189"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/S1474-4422(10)70159-9","article-title":"The diagnosis of young-onset dementia","volume":"9","author":"Rossor","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_13","unstructured":"NHS Digital (2025, June 23). Primary Care Dementia Data, May 2025. Available online: https:\/\/digital.nhs.uk\/data-and-information\/publications\/statistical\/primary-care-dementia-data\/may-2025."},{"key":"ref_14","unstructured":"Algin, D.I., Adapinar, D.O., and Erdinc, O.O. (2020). EEG Biomarker for Alzheimer\u2019s Disease. Neurodegenerative Diseases, IntechOpen."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1016\/S0140-6736(06)68542-5","article-title":"Mild cognitive impairment","volume":"367","author":"Gauthier","year":"2006","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.clnesp.2025.03.040","article-title":"Nutritional interventions for preventing cognitive decline in patients with mild cognitive impairment and Alzheimer\u2019s disease: A comprehensive network meta-analysis and Mendelian Randomization study","volume":"67","author":"He","year":"2025","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"478","DOI":"10.3988\/jcn.2023.0289","article-title":"Predicting the Progression of Mild Cognitive Impairment to Alzheimer\u2019s Dementia Using Recurrent Neural Networks with a Series of Neuropsychological Tests","volume":"20","author":"Park","year":"2024","journal-title":"J. Clin. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cardelo, M.P., Corina, A., Leon-Acu\u00f1a, A., Quintana-Navarro, G.M., Alcala-Diaz, J.F., Rangel-Zu\u00f1iga, O.A., Camargo, A., Conde-Gavilan, C., Carmona-Medialdea, C., and Vallejo-Casas, J.A. (2022). Effect of the Mediterranean diet and probiotic supplementation in the management of mild cognitive impairment: Rationale, methods, and baseline characteristics. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.1037842"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.jamda.2016.06.020","article-title":"Spontaneous Reversion of Mild Cognitive Impairment to Normal Cognition: A Systematic Review of Literature and Meta-Analysis","volume":"17","author":"Canevelli","year":"2016","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s40120-020-00227-y","article-title":"Potential Neuroregenerative and Neuroprotective Effects of Uridine\/Choline-Enriched Multinutrient Dietary Intervention for Mild Cognitive Impairment: A Narrative Review","volume":"10","author":"Baumel","year":"2021","journal-title":"Neurol. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Manacharoen, A., Jayanama, K., Ruangritchankul, S., Vathesatogkit, P., Sritara, P., and Warodomwichit, D. (2023). Association of body mass index and dietary intake with mild cognitive impairment and dementia: A retrospective cohort study. BMC Geriatr., 23.","DOI":"10.1186\/s12877-022-03700-5"},{"key":"ref_22","first-page":"139","article-title":"Nutrients required for phospholipid synthesis are lower in blood and cerebrospinal fluid in mild cognitive impairment and Alzheimer\u2019s disease dementia","volume":"8","author":"Slot","year":"2017","journal-title":"Alzheimer\u2019s Dement. Diagn. Assess. Dis. Monit."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"69","DOI":"10.31887\/DCNS.2019.21.1\/nscarmeas","article-title":"Dietary interventions in mild cognitiveimpairment and dementia","volume":"21","author":"Vlachos","year":"2019","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1146\/annurev-nutr-071715-050947","article-title":"Homocysteine, B Vitamins, and Cognitive Impairment","volume":"36","author":"Smith","year":"2016","journal-title":"Annu. Rev. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"622","DOI":"10.2174\/1567205016666190725144629","article-title":"Effects of Folic Acid and Vitamin B12, Alone and in Combination on Cognitive Function and Inflammatory Factors in the Elderly with Mild Cognitive Impairment: A Single-blind Experimental Design","volume":"16","author":"Ma","year":"2019","journal-title":"Curr. Alzheimer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1007\/s10072-016-2647-1","article-title":"Vitamin D deficiency might pose a greater risk for ApoE\u025b4 non-carrier Alzheimer\u2019s disease patients","volume":"37","author":"Dursun","year":"2016","journal-title":"Neurol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1179\/1476830512Y.0000000013","article-title":"Association between vitamin A, vitamin E and apolipoprotein E status with mild cognitive impairment among elderly people in low-cost residential areas","volume":"16","author":"Shahar","year":"2013","journal-title":"Nutr. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kim, S.G., Keum, M., Choe, Y.M., Suh, G.H., Lee, B.C., Kim, H.S., Lee, J.H., Hwang, J., Yi, D., and Kim, J.W. (2025). Selenium and Episodic Memory: The Moderating Role of Apolipoprotein E epsilon4. Nutrients, 17.","DOI":"10.3390\/nu17030595"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.jalz.2018.12.017","article-title":"A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment","volume":"15","author":"Fortier","year":"2019","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gordon, S., Hoey, L., McNulty, H., Keenan, J., Pangilinan, F., Brody, L.C., Ward, M., Strain, J.J., McAnena, L., and McCann, A. (2025). Associations of one-carbon metabolism, related B-vitamins and ApoE genotype with cognitive function in older adults: Identification of a novel gene-nutrient interaction. BMC Med., 23.","DOI":"10.1186\/s12916-025-04276-8"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1002\/alz.12206","article-title":"A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT","volume":"17","author":"Fortier","year":"2021","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"n160","DOI":"10.1136\/bmj.n160","article-title":"PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"320","DOI":"10.4103\/0972-2327.157255","article-title":"Effect of apolipoprotein E (APO E) polymorphism on leptin in Alzheimer\u2019s disease","volume":"18","author":"Agarwal","year":"2015","journal-title":"Ann. Indian Acad. Neurol."},{"key":"ref_34","unstructured":"The EndNote Team (2013). EndNote, Clarivate."},{"key":"ref_35","unstructured":"Higgins, J.P.T., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V.A. (2024). Chapter 8: Assessing risk of bias in a randomized trial. Cochrane Handbook for Systematic Reviews of Interventions Version 6.5, Cochrane."},{"key":"ref_36","unstructured":"Higgins, J.P.T., Chandler, J., Cumpston, M., Li, T., Page, M.J., and Welch, V.A. (2024). Chapter 25: Assessing risk of bias in a non-randomized study [last updated October 2019]. Cochrane Handbook for Systematic Reviews of Interventions Version 6.5, Cochrane."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"205","DOI":"10.3233\/JAD-2010-090940","article-title":"B-vitamins and fatty acids in the prevention and treatment of Alzheimer\u2019s disease and dementia: A systematic review","volume":"22","author":"Dangour","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.arr.2016.02.002","article-title":"Apolipoprotein E (APOE) \u03b54 and episodic memory decline in Alzheimer\u2019s disease: A review","volume":"27","author":"Antoine","year":"2016","journal-title":"Ageing Res. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Behl, C. (2023). Beyond APP, PSEN1, PSEN2, and APOE: What Else Does the Genome Tell Us?. Alzheimer\u2019s Disease Research: What Has Guided Research So Far and Why It Is High Time for a Paradigm Shift, Springer International Publishing.","DOI":"10.1007\/978-3-031-31570-1_16"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1093\/brain\/awaf038","article-title":"The landscape of autosomal-dominant Alzheimer\u2019s disease: Global distribution and age of onset","volume":"148","author":"Liu","year":"2025","journal-title":"Brain"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lanoisel\u00e9e, H.-M., Nicolas, G., Wallon, D., Rovelet-Lecrux, A., Lacour, M., Rousseau, S., Richard, A.-C., Pasquier, F., Rollin-Sillaire, A., and Martinaud, O. (2017). APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med., 14.","DOI":"10.1371\/journal.pmed.1002270"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/8\/1263\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:11:23Z","timestamp":1776917483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/8\/1263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,16]]},"references-count":41,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["nu18081263"],"URL":"https:\/\/doi.org\/10.3390\/nu18081263","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,16]]}}}