The Impact of Omega-3 Fatty Acids, Polyphenols and Vitamin D on Neurodegenerative Diseases: A Meta-Analysis

Abstract

Aim: This study is aimed to to assess the impact of vitamin D, omega-3 fatty acids (ω-3), and polyphenols on cognitive functioning, clinical outcomes, and inflammatory biomarkers in patients diagnosed with Alzheimer’s disease (AD), Parkinson’s disease (PD), and Multiple Sclerosis (MS). Method: A systematic search was conducted in the PubMed, Scopus, and Google Scholar databases. Only clinical trials and randomized controlled trials (RCTs) were included. A total of 689 studies published between 2000 and 2025 were reviewed, and 14 studies that met the inclusion criteria were analyzed. Effect sizes were calculated using Hedges’ g value. Fixed and random effects models were used depending on heterogeneity. Funnel plots were used to assess publication bias. All statistical analyses were performed using the Comprehensive Meta-Analysis (CMA) program. Results: Vitamin D supplementation significantly raised blood 25-hydroxyvitamin D [25(OH)D] levels (g = 1.589, p< .001). The Mini-Mental State Examination (MMSE) showed no significant cognitive effects of omega-3 polyunsaturated fatty acids and polyphenols (p> 0.05). One study indicated that ellagic acid reduced Expanded Disability Status Scale (EDSS) scores, while vitamin D and omega-3 supplementation did not. Some studies showed considerable reductions in IL-6 and TNF-α levels, but the meta-analysis found no statistical significance. A substantial decrease in TNF-α was seen in the fixed effects model (p= .0029), but not in the random effects model (p= .132) Conclusion: Vitamin D supplementation markedly elevated serum 25(OH)D levels, indicating its potential as an effective intervention in neurodegenerative processes. The impact of omega-3 fatty acids and polyphenols on cognitive and clinical outcomes was observed to be inconsistent. Additional high-quality, long-term randomized controlled trials are necessary to more accurately assess the clinical efficacy of these compounds in neurodegenerative diseases.

Keywords

• Vitamin D
• omega-3 fatty acids
• polyphenols
• neurodegenerative diseases
• meta-analysis

Omega-3 Yağ Asitleri, Polifenoller ve D Vitaminin Nörodejeneratif Hastalıklar Üzerindeki Etkisi: Bir Meta-Analiz

Öz

Amaç: Bu çalışmanın amacı, Alzheimer hastalığı, Parkinson hastalığı ve Multipl Skleroz tanısı almış bireylerde D vitamini, omega-3 yağ asitleri ve polifenollerin bilişsel fonksiyonlar, klinik sonuçlar ve inflamatuar biyobelirteçler üzerindeki etkilerini değerlendirmektir. Yöntem: Scopus, PubMed ve Google Scholar veri tabanlarında sistematik bir arama yapıldı. Sadece klinik çalışmalar ve randomize kontrollü çalışmalar dahil edildi. 2000 ile 2025 yılları arasında yayınlanan toplam 689 çalışma incelendi ve dahil etme kriterlerini karşılayan 14 çalışma analiz edildi. Etki büyüklükleri Hedges’g değeri kullanılarak hesaplandı. Heterojenliğe bağlı olarak sabit ve rastgele etkiler modelleri kullanıldı. Yayın yanlılığını değerlendirmek için huni grafikleri kullanıldı. Tüm istatiksel analizler Comprehensive Meta-Analysis (CMA) programı kullanılarak yapılmıştır. Bulgular: D vitamini takviyesi, kan 25-hidroksivitamin D [25(OH)D] seviyelerini önemli ölçüde yükseltti (g=1,589, p<,001). Mini-Mental Durum Testi, omega-3 çoklu doymamış yağ asitleri ve polifenollerin bilişsel açıdan önemli bir etkisini göstermedi (p>0,05). Bir çalışma, ellajik asidin Genişletilmiş Engellilik Durumu Ölçeği puanlarını düşürdüğünü, ancak D vitamini ve omega-3 takviyesinin düşürmediğini göstermiştir. Bazı çalışmalar IL-6 ve TNF-α seviyelerinde önemli düşüşler gösterdi, ancak meta-analiz istatiksel olarak anlamlı sonuç bulunamadı. Sabit etkiler modelinde TNF-α’da önemli bir azalma görülürken (p=,0029), rastgele etkiler modelinde görülmemiştir (p=,132). Sonuç: D vitamini takviyesi serum 25(OH)D düzeylerini belirgin şekilde yükseltmiş, bu da nörodejeneratif süreçlerde etkili bir müdahale olarak potansiyelini göstermektedir. Omega-3 yağ asitlerinin ve polifenollerin bilişsel ve klinik sonuçlar üzerindeki etkisinin tutarsız olduğu gözlemlenmiştir. Bu bileşiklerin nörodejeneratif hastalıklardaki klinik etkinliğini daha doğru bir şekilde değerlendirmek için daha fazla, yüksek, kaliteli ve uzun vadeli randomize kontrollü çalışmalara ihtiyaç vardır.

Anahtar Kelimeler

• D vitamini
• omega-3 yağ asitleri
• polifenoller
• nörodejeneratif hastalıklar
• meta-analiz

References

1. 1. Guan D, Liang C, Zheng D, et al. The role of mitochondrial remodeling in neurodegenerative diseases. Neurochem Int. 2025;183.
2. 2. Nichols E, Szoeke CEI, Vollset SE, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(1):88-106.
3. 3. Collaborators* G 2021 NSD. Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet. 2024;23:1990-2021.
4. 4. World Health Organization. Public Health Response to Dementia.; 2021.
5. 5. Grisold W, Dodick D, Guekht A, Lewis S, Logan A, Wijnerate T. The World Federation of Neurology: Brain health for all ages 2025. J Neurol Sci. 2025;474:123530.
6. 6. Jones A, Ali MU, Kenny M, et al. Potentially modifiable risk factors for dementia and mild cognitive ımpairment: An umbrella review and meta-analysis. Dement Geriatr Cogn Disord. 2024;53(2):91-106. doi: 10.1159/000536643.
7. 7. Spencer PS, Berntsson SG, Buguet A, et al. Brain health: Pathway to primary prevention of neurodegenerative disorders of environmental origin. J Neurol Sci. 2025;468.
8. 8. Gillette-Guyonnet S, Secher M, Vellas B. Nutrition and neurodegeneration: Epidemiological evidence and challenges for future research. Br J Clin Pharmacol. 2013;75(3):738-755. doi: 10.1111/bcp.12058.

9. 9. Shen L, Ji HF. Vitamin D deficiency is associated with increased risk of Alzheimer’s disease and dementia: Evidence from meta-analysis. Nutr J. 2015;14(1):1-5.
10. 10. Bianchi VE, Herrera PF, Laura R. Effect of nutrition on neurodegenerative diseases. A systematic review. Nutr Neurosci. 2021;24(10):810-834.
11. 11. Devassy JG, Leng S, Gabbs M, Monirujjaman M, Aukema HM. Omega-3 polyunsaturated fatty acids and oxylipins in neuroinflammation and management of alzheimer disease. Adv Nutr. 2016;7(5):905-916. doi: 10.3945/an.116.012187.
12. 12. Scalbert A, Manach C, Morand C, Rémésy C, Jiménez L. Dietary polyphenols and the prevention of diseases. Crit Rev Food Sci Nutr. 2005;45(4):287-306.
13. 13. Arias-Sánchez RA, Torner L, Fenton Navarro B. Polyphenols and neurodegenerative diseases: Potential effects and mechanisms of neuroprotection. Molecules. 2023;28(14):1-15. doi: 10.3390/molecules28145415.
14. 14. Turcu-Stiolica A, Naidin MS, Halmagean S, Ionescu AM, Pirici I. The impact of the dietary intake of vitamin B12, folic acid, and vitamin D3 on homocysteine levels and the health-related quality of life of levodopa-treated patients with parkinson’s disease—a pilot study in Romania. Diagnostics. 2024;14(15). doi: 10.3390/diagnostics14151609.
15. 15. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ. 2021;372. doi: 10.1136/bmj.n71.
16. 16. Booth A, Clarke M, Dooley G, et al. PROSPERO at one year: An evaluation of its utility. Syst Rev. 2013;2:4. doi: 10.1186/2046-4053-2-4.
17. 17. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to Meta-Analysis. New Jersey: John Wiley & Sons; 2009.
18. 18. Hedges L V., Olkin I. Statistical methods for meta-analysis. New York: Academic Press; 2014.
19. 19. Jafari Karegar S, Aryaeian N, Hajiluian G, et al. Ellagic acid effects on disease severity, levels of cytokines and T-bet, RORγt, and GATA3 genes expression in multiple sclerosis patients: A multicentral-triple blind randomized clinical trial. Front Nutr. 2023;10.
20. 20. Mosayebi G, Ghazavi A, Ghasami K, Jand Y, Kokhaei P. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest. 2011;40(6):627-639.
21. 21. Ramirez-Ramirez V, Macias-Islas MA, Ortiz GG, et al. Efficacy of fish oil on serum of TNF α, IL-1 β, and IL-6 oxidative stress markers in multiple sclerosis treated with interferon beta-1b. Oxid Med Cell Longev. 2013;2013. doi: 10.1155/2013/709493.
22. 22. Torkildsen Ø, Wergeland S, Bakke S, et al. ω-3 fatty acid treatment in multiple sclerosis (OFAMS study): A randomized, double-blind, placebo-controlled trial. Arch Neurol. 2012;69(8):1044-1051. doi: 10.1001/archneurol.2012.283.
23. 23. Kampman MT, Steffensen LH, Mellgren SI, Jørgensen L. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: Exploratory outcomes from a double-blind randomised controlled trial. Mult Scler J. 2012;18(8):1144-1151. doi: 10.1177/1352458511434607.
24. 24. Camu W, Lehert P, Pierrot-Deseilligny C, et al. Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE). Neurol Neuroimmunol NeuroInflammation. 2019;6(5):1-7. doi: 10.1212/NXI.0000000000000597.
25. 25. Chiu CC, Su KP, Cheng TC, et al. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: A preliminary randomized double-blind placebo-controlled study. Prog Neuro-Psychopharmacology Biol Psychiatry. 2008;32(6):1538-1544. doi: 10.1016/j.pnpbp.2008.05.015.
26. 26. Loukou S, Papantoniou G, Pantazaki A, Tsolaki M. The role of greek olive leaf extract in patients with mild alzheimer’s disease (the golden study): A randomized controlled clinical trial. Neurol Int. 2024;16(6):1247-1265.
27. 27. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, et al. ω-3 fatty acid treatment in 174 patients with mild to moderate alzheimer disease: OmegAD study - A randomized double-blind trial. Arch Neurol. 2006;63(10):1402-1408.
28. 28. Tofiq A, Zetterberg H, Blennow K, et al. Effects of peroral omega-3 fatty acid supplementation on cerebrospinal fluid biomarkers in patients with alzheimer’s disease: A randomized controlled trial- The OmegAD study. J Alzheimer’s Dis. 2021;83(3):1291-1301. doi: 10.3233/JAD-210007.
29. 29. Bytowska ZK, Korewo-Labelle D, Kowalski K, et al. Impact of 12 weeks of vitamin d3 administration in parkinson’s patients with deep brain stimulation on kynurenine pathway and ınflammatory status. Nutrients. 2023;15(17). doi: 10.3390/nu15173839.
30. 30. Jia J, Hu J, Huo X, Miao R, Zhang Y, Ma F. Effects of Vitamin D supplementation on cognitive function and blood Aβ-related biomarkers in older adults with Alzheimer’s disease: A randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry. 2019;90(12):1347-1352. doi: 10.1136/jnnp-2018-320199.
31. 31. Røsjø E, Steffensen LH, Jørgensen L, et al. Vitamin D supplementation and systemic inflammation in relapsing-remitting multiple sclerosis. J Neurol. 2015;262(12):2713-21.
32. 32. Freund-Levi Y, Hjorth E, Lindberg C, et al. Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in alzheimer’s disease: The omegad study. Dement Geriatr Cogn Disord. 2009;27(5):481-490.