{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T03:22:41Z","timestamp":1790220161342,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,6]],"date-time":"2021-03-06T00:00:00Z","timestamp":1614988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Vitamin D and cognition is a popular association, which led to a remarkable body of literature data in the past 50 years. The brain can synthesize, catabolize, and receive Vitamin D, which has been proved to regulate many cellular processes in neurons and microglia. Vitamin D helps synaptic plasticity and neurotransmission in dopaminergic neural circuits and exerts anti-inflammatory and neuroprotective activities within the brain by reducing the synthesis of pro-inflammatory cytokines and the oxidative stress load. Further, Vitamin D action in the brain has been related to the clearance of amyloid plaques, which represent a feature of Alzheimer Disease (AD), by the immune cell. Based on these considerations, many studies have investigated the role of circulating Vitamin D levels in patients affected by a cognitive decline to assess Vitamin D\u2019s eventual role as a biomarker or a risk factor in AD. An association between low Vitamin D levels and the onset and progression of AD has been reported, and some interventional studies to evaluate the role of Vitamin D in preventing AD onset have been performed. However, many pitfalls affected the studies available, including substantial discrepancies in the methods used and the lack of standardized data. Despite many studies, it remains unclear whether Vitamin D can have a role in cognitive decline and AD. This narrative review aims to answer two key questions: whether Vitamin D can be used as a reliable tool for diagnosing, predicting prognosis and response to treatment in AD patients, and whether it is a modifiable risk factor for preventing AD onset.<\/jats:p>","DOI":"10.3390\/brainsci11030334","type":"journal-article","created":{"date-parts":[[2021,3,7]],"date-time":"2021-03-07T20:20:43Z","timestamp":1615148443000},"page":"334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["The Role of Vitamin D as a Biomarker in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1723-3305","authenticated-orcid":false,"given":"Giulia","family":"Bivona","sequence":"first","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna","family":"Lo Sasso","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy"},{"name":"Department of Laboratory Medicine, AOUP \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina Maria","family":"Gambino","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosaria Vincenza","family":"Giglio","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Scazzone","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Agnello","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6120-9041","authenticated-orcid":false,"given":"Marcello","family":"Ciaccio","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy"},{"name":"Department of Laboratory Medicine, AOUP \u201cP. Giaccone\u201d, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1080\/01616412.2019.1622872","article-title":"Vitamin D and the nervous system","volume":"41","author":"Bivona","year":"2019","journal-title":"Neurol. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bivona, G., Agnello, L., Bellia, C., Iacolino, G., Scazzone, C., Lo Sasso, B., and Ciaccio, M. (2019). Non-Skeletal Activities of Vitamin D: From Physiology to Brain Pathology. Medicina, 55.","DOI":"10.3390\/medicina55070341"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/s41574-019-0312-5","article-title":"New aspects of vitamin D metabolism and action\u2014Addressing the skin as source and target","volume":"16","author":"Bikle","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.bonr.2018.02.004","article-title":"Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review","volume":"8","author":"Bikle","year":"2018","journal-title":"Bone Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"331","DOI":"10.5114\/ceji.2018.80053","article-title":"The immunological implication of the new vitamin D metabolism","volume":"43","author":"Bivona","year":"2018","journal-title":"Cent. Eur. J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"317","DOI":"10.3389\/fendo.2019.00317","article-title":"Vitamin D binding protein, total and free vitamin D levels in different physiological and pathophysiological conditions","volume":"10","author":"Bikle","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.plipres.2016.09.003","article-title":"DHCR7: A vital enzyme switch between cholesterol and vitamin D production","volume":"64","author":"Prabhu","year":"2016","journal-title":"Prog. Lipid Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17541","DOI":"10.1074\/jbc.M117.806901","article-title":"A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation","volume":"292","author":"Meyer","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1210\/jc.2011-0385","article-title":"Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline","volume":"96","author":"Holick","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.cca.2019.07.022","article-title":"Standardized measurement of circulating vitamin D [25(OH)D] and its putative role as a serum biomarker in Alzheimer\u2019s disease and Parkinson\u2019s disease","volume":"497","author":"Bivona","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"312","DOI":"10.17269\/s41997-019-00290-5","article-title":"Vitamin D status, cognitive decline and incident dementia: The Canadian Study of Health and Aging","volume":"111","author":"Duchaine","year":"2020","journal-title":"Can. J. Public Health"},{"key":"ref_12","first-page":"75","article-title":"Relationship between 25-hydroxy vitamin D and cognitive status in older adults: The COGNIDAGE study","volume":"107","author":"Manzo","year":"2016","journal-title":"Recenti Prog. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e19293","DOI":"10.1097\/MD.0000000000019293","article-title":"Association between vitamin D deficiency and cognitive function in the elderly Korean population: A Korean frailty and aging cohort study","volume":"99","author":"Lee","year":"2020","journal-title":"Medicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1212\/WNL.0000000000000755","article-title":"Vitamin D and the risk of dementia and Alzheimer disease","volume":"83","author":"Littlejohns","year":"2014","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"989","DOI":"10.3233\/JAD-170407","article-title":"Vitamin D and the risk of dementia: The Rotterdam study","volume":"60","author":"Licher","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1212\/WNL.0b013e3181beecb7","article-title":"25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services","volume":"74","author":"Buell","year":"2010","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.jalz.2017.03.003","article-title":"Associations of lower vitamin D concentrations with cognitive decline and long-term risk of dementia and Alzheimer\u2019s disease in older adults","volume":"13","author":"Feart","year":"2017","journal-title":"Alzheimers Dement."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e00936","DOI":"10.1002\/brb3.936","article-title":"Serum vitamin D in patients with mild cognitive impairment and Alzheimer\u2019s disease","volume":"8","author":"Ouma","year":"2018","journal-title":"Brain Behav."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.jalz.2013.05.1765","article-title":"Reduced 25-hydroxyvitamin D and risk of Alzheimer\u2019s disease and vascular dementia","volume":"10","author":"Afzal","year":"2014","journal-title":"Alzheimers Dement."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ertilav, E., Barcin, N.E., and Ozdem, S. (2020). Comparison of Serum Free and Bioavailable 25-Hydroxyvitamin D Levels in Alzheimer\u2019s Disease and Healthy Control Patients. Lab. Med., lmaa066.","DOI":"10.1093\/labmed\/lmaa066"},{"key":"ref_21","first-page":"381","article-title":"Association of Vitamin D with Mild Cognitive Impairment and Alzheimer\u2019s Dementia in Older Mexican Adults","volume":"71","year":"2019","journal-title":"Rev. Investig. Clin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1111\/ggi.13821","article-title":"Effect of vitamin D on cognitive function and white matter hyperintensity in patients with mild Alzheimer\u2019s disease","volume":"20","author":"Shih","year":"2020","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"717","DOI":"10.3233\/JAD-160393","article-title":"Normal Vitamin Levels and Nutritional Indices in Alzheimer\u2019s Disease Patients with Mild Cognitive Impairment or Dementia with Normal Body Mass Indexes","volume":"55","author":"Ulstein","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"936","DOI":"10.3945\/ajcn.116.141531","article-title":"Vitamin D is not associated with incident dementia or cognitive impairment: An 18-y follow-up study in community-living old men","volume":"105","author":"Olsson","year":"2017","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3233\/JAD-150991","article-title":"Association of serum vitamin D with the risk of incident dementia and subclinical indices of brain aging: The Framingham Heart Study","volume":"51","author":"Karakis","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1212\/WNL.0b013e31826c197f","article-title":"Vitamin D, cognition, and dementia: A systematic review and meta-analysis","volume":"79","author":"Balion","year":"2012","journal-title":"Neurology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/jnr.24133","article-title":"Association of CYP2R1 rs10766197 with MS risk and disease progression","volume":"96","author":"Scazzone","year":"2018","journal-title":"J. Neurosci. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3233\/JAD-2012-110560","article-title":"Genomic and non genomic signaling induced by 1\u03b1,25(OH)2-vitamin D3 promotes the recovery of amyloid-\u03b2 phagocytosis by Alzheimer\u2019s disease macrophages","volume":"29","author":"Mizwicki","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_29","first-page":"192747","article-title":"Vitamin D and Alzheimer\u2019s Disease: Neurocognition to Therapeutics","volume":"2015","author":"Banerjee","year":"2015","journal-title":"Int. J. Alzheimers. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"703","DOI":"10.3233\/JAD-2009-1080","article-title":"1\u03b1,25-dihydrox-yvitamin D3 interacts with curcuminoids to stimulate amyloid-\u03b2clearance by macrophages of alzheimer\u2019s disease patients","volume":"17","author":"Masoumi","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"295","DOI":"10.3233\/JAD-2011-101986","article-title":"Vitamin D3-enriched diet correlates with a decrease of amyloid plaques in the brain of A\u03b2PP transgenic mice","volume":"25","author":"Yu","year":"2011","journal-title":"J. Alzheimers Dis."},{"key":"ref_32","first-page":"10","article-title":"The concept of multiple vitamin D signaling pathways","volume":"1","author":"Carlberg","year":"1996","journal-title":"J. Investig. Dermatol. Symp. Proc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1126\/science.283.5406.1317","article-title":"Convergence of transforming growth factor-\u03b2and vitamin D signaling pathways on SMAD transcriptional coactivators","volume":"283","author":"Yanagisawa","year":"1999","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1080\/00365513.2020.1740939","article-title":"Diagnostic accuracy of cerebrospinal fluid biomarkers measured by chemiluminescent enzyme immunoassay for Alzheimer disease diagnosis","volume":"80","author":"Agnello","year":"2020","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"477","DOI":"10.3233\/JAD-2011-110149","article-title":"A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer\u2019s disease","volume":"26","author":"Stein","year":"2011","journal-title":"J. Alzheimers Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1007\/s00198-008-0619-x","article-title":"Rapid correction of low vitamin D status in nursing home residents","volume":"19","author":"Przybelski","year":"2008","journal-title":"Osteoporos Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1111\/jgs.12032","article-title":"Calcium and vitamin D supplementation and cognitive impairment in the women\u2019s health initiative","volume":"60","author":"Rossom","year":"2012","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_38","first-page":"175","article-title":"Effects of a six-month multi-ingredient nutrition supplement intervention of omega-3 polyunsaturated fatty acids, vitamin D, resveratrol, and whey protein on cognitive function in older adults: A randomized, double-blind, controlled trial","volume":"5","author":"Moran","year":"2018","journal-title":"J. Prev. Alzheimers Dis."},{"key":"ref_39","first-page":"1347","article-title":"Effects of vitamin D supplementation on cognitive function and blood A\u03b2-related biomarkers in older adults with Alzheimer\u2019s disease: A randomized, double-blind, placebo-controlled trial","volume":"90","author":"Jia","year":"2019","journal-title":"Neurol. Neurosurg. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1097\/WNN.0b013e31826df647","article-title":"Effectiveness of the combination of memantine plus vitamin D on cognition in patients with Alzheimer disease: A pre-post pilot study","volume":"25","author":"Annweiler","year":"2012","journal-title":"Cogn. Behav. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"133","DOI":"10.3177\/jnsv.63.133","article-title":"Medium-Chain Triglycerides in Combination with Leucine and Vitamin D Benefit Cognition in Frail Elderly Adults: A Randomized Controlled Trial","volume":"63","author":"Abe","year":"2017","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1001\/jama.2020.16909","article-title":"Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial","volume":"324","author":"Vellas","year":"2020","journal-title":"JAMA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jns.2018.11.020","article-title":"Vitamin D supplementation has no effect on cognitive performance after four months in mid-aged and older subjects","volume":"396","author":"Jorde","year":"2019","journal-title":"J. Neurol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.3233\/JAD-200926","article-title":"Vitamin D Supplementation Improves Cognitive Function Through Reducing Oxidative Stress Regulated by Telomere Length in Older Adults with Mild Cognitive Impairment: A 12-Month Randomized Controlled Trial","volume":"78","author":"Yang","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_45","first-page":"CD011906","article-title":"Vitamin and mineral supplementation for maintaining cognitive function in cognitively healthy people in mid and late life","volume":"12","author":"Rutjes","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.jamda.2019.09.021","article-title":"Vitamin D Supplementation for Extraskeletal Indications in Older Persons","volume":"21","author":"Bode","year":"2020","journal-title":"J. Am. Med. Dir. 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