Natural Health Products in the Prevention and Management of Alzheimer’s Disease: A Systematic Review of Randomized Clinical Trials
Source abstract
Abstract
Supplementation with natural compounds, referred to as Natural Health Products (NHPs), is emerging as an applicable strategy in all phases of Alzheimer’s disease (AD) management, alongside pharmacological therapy. Several studies have investigated the potential of NHPs to modulate neurochemical and inflammatory processes associated with clinical decline; however, the results remain inconclusive. To evaluate the influence of NHPs on the clinical outcomes of AD patients, a systematic review was performed by searching the PubMed, Scopus, Cochrane, and Clinical Trials.gov databases for randomized clinical trials (RCTs) exploring the effects associated with NHP supplementation for the treatment of AD. Out of the 34 RCTs analyzed, 50% reported improvements in cognitive function and reductions in neuroinflammatory markers following NHP supplementation, suggesting a potential but inconsistent therapeutic effect. The strongest evidence of benefit in AD patients was found with the use of vitamin D, selenium, and probiotics. A certain incidence of depressive disorders and delirium highlights the necessity to better evaluate the safety and tolerability of B vitamin supplements. Overall, this systematic review found mixed results regarding the use of NHPs in the management of AD. Further evidence is needed to support their use in clinical practice.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Medicinal Plants and Bioactive Compounds
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Medicine, Surgery, and Dentistry, Scuola Medica Salernitana, University of Salerno, 84081 Baronissi, Italy
Clinical Pharmacology Unit, San Giovanni di Dio e Ruggi d’Aragona University Hospital, 84131 Salerno, Italy
Postgraduate School of Clinical Pharmacology and Toxicology, University of Salerno, 84081 Baronissi, Italy
PhD School “Clinical and Translational Oncology (CTO)”, Scuola Superiore Meridionale, University of Naples “Federico II”, 80138 Naples, Italy
Infectious Diseases Unit, San Giovanni di Dio e Ruggi d’Aragona University Hospital, 84131 Salerno, Italy
Department of Translational Medical Sciences, University of Naples “Federico II”, 80131 Naples, Italy
References (86)
Show source-provided references
1. (2025, February 18). Available online: https://www.who.int/news-room/fact-sheets/detail/dementia.
2. Estimation of the Global Prevalence of Dementia in 2019 and Forecasted Prevalence in 2050: An Analysis for the Global Burden of Disease Study 201910.1016/S2468-2667(21)00249-8 ↗
3. Risk Factors for Alzheimer’s Disease: An Epidemiological Study10.2174/1567205018666210820124135 ↗
4. (2025, February 19). Available online: https://www.who.int/news/item/07-12-2017-dementia-number-of-people-affected-to-triple-in-next-30-years.
5. Is Alzheimer’s Disease Risk Modifiable?10.3233/JAD181028 ↗
6. Role of genes and environments for explaining Alzheimer disease10.1001/archpsyc.63.2.168 ↗
7. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk10.1038/s41588-018-0311-9 ↗
8. New Frontiers in the Prevention, Diagnosis, and Treatment of Alzheimer’s Disease10.3233/JAD-201059 ↗
9. Breijyeh, Z., and Karaman, R. (2020). Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules, 25.10.3390/molecules25245789 ↗
10. Yiannopoulou, K.G., Anastasiou, A.I., Zachariou, V., and Pelidou, S.H. (2019). Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research. Biomedicines, 7.10.20944/preprints201909.0270.v1 ↗
11. Conti, V., Polcaro, G., De Bellis, E., Donnarumma, D., De Rosa, F., Stefanelli, B., Corbi, G., Sabbatino, F., and Filippelli, A. (2024). Natural Health Products for Anti-Cancer Treatment: Evidence and Controversy. J. Pers. Med., 14.10.3390/jpm14070685 ↗
12. The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer’s disease: Acting separately or synergistically?10.1016/j.plipres.2015.12.003 ↗
13. Vitamin E, memantine, and Alzheimer disease10.1001/jama.2013.282835 ↗
14. Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia10.1186/s40780-015-0014-7 ↗
15. Ginkgo biloba in Alzheimer’s disease: A systematic review10.1007/s10354-010-0844-8 ↗
16. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo10.1074/jbc.M404751200 ↗
17. Brain atrophy in cognitively impaired elderly: The importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial10.3945/ajcn.114.103283 ↗
18. Drug-Drug Interactions Between HIV Antivirals and Concomitant Drugs in HIV Patients: What We Know and What We Need to Know
19. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomised, double blind, controlled trial10.1016/S0140-6736(07)60109-3 ↗
20. (2025, February 18). Available online: https://www.prisma-statement.org/prisma-2020-flow-diagram.
21. Assessing the quality of reports of randomized clinical trials: Is blinding necessary?10.1016/0197-2456(95)00134-4 ↗
22. Mielech, A., Puścion-Jakubik, A., Markiewicz-Żukowska, R., and Socha, K. (2020). Vitamins in Alzheimer’s Disease-Review of the Latest Reports. Nutrients, 12.10.3389/fphar.2021.738549 ↗
23. Shah, H., Dehghani, F., Ramezan, M., Gannaban, R.B., Haque, Z.F., Rahimi, F., Abbasi, S., and Shin, A.C. (2023). Revisiting the Role of Vitamins and Minerals in Alzheimer’s Disease. Antioxidants, 12.10.3390/antiox12020415 ↗
24. Homocysteine and Dementia: An International Consensus Statement10.3233/JAD-171042 ↗
25. (2025, February 18). Available online: https://www.micuro.it/enciclopedia/anatomia/omocisteina?utm_source.
26. Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: A randomized controlled trial10.1001/jama.300.15.1774 ↗
27. Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer’s disease: A 26-week, randomized, double-blind, placebo-controlled study in Taiwanese patients10.1016/j.clinthera.2007.10.012 ↗
28. Effects of Folic Acid and Vitamin B12 Supplementation on Cognitive Impairment and Inflammation in Patients with Alzheimer’s Disease: A Randomized, Single-Blinded, Placebo-Controlled Trial10.14283/jpad.2021.22 ↗
29. Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer’s disease: A placebo-controlled pilot study10.1177/1533317508325094 ↗
30. Moretti, R., Morelli, M.E., and Caruso, P. (2018). Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact. Int. J. Mol. Sci., 19.10.20944/preprints201806.0460.v1 ↗
31. 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
32. A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer’s disease10.3233/JAD-2011-110149 ↗
33. (2025, February 18). Available online: https://www.centroalzheimer.org/la-somministrazione-di-insulina-intranasale-come-terapia-per-la-malattia-di-alzheimer.
34. Plasma nutrient status of patients with Alzheimer’s disease: Systematic review and meta-analysis10.1016/j.jalz.2013.05.1771 ↗
35. Do low-serum vitamin E levels increase the risk of Alzheimer disease in older people? Evidence from a meta-analysis of case-control studies10.1002/gps.4780 ↗
36. A meta-analysis of peripheral tocopherol levels in age-related cognitive decline and Alzheimer’s disease10.1080/1028415X.2019.1681066 ↗
37. Alzheimer’s Disease Cooperative Study. Antioxidants for Alzheimer disease: A randomized clinical trial with cerebrospinal fluid biomarker measures10.1001/archneurol.2012.85 ↗
38. Effect of vitamin E and memantine on functional decline in Alzheimer disease: The TEAM-AD VA cooperative randomized trial10.1001/jama.2013.282834 ↗
39. Donepezil, rivastigmine, and vitamin E in Alzheimer disease: A combined P300 event-related potentials/neuropsychologic evaluation over 6 months10.1097/00002826-200101000-00007 ↗
40. Neuroinflammation Induces Neurodegeneration
41. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease10.1136/jnnp.74.6.788 ↗
42. The role of peripheral inflammatory markers in dementia and Alzheimer’s disease: A meta-analysis10.1093/gerona/gls187 ↗
43. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina10.1016/S0163-7827(00)00017-5 ↗
44. Omega-3 fatty acid supplementation effects on weight and appetite in patients with Alzheimer’s disease: The omega-3 Alzheimer’s disease study10.1111/j.1532-5415.2008.02055.x ↗
45. Effects on transthyretin in plasma and cerebrospinal fluid by DHA-rich n—3 fatty acid supplementation in patients with Alzheimer’s disease: The OmegAD study10.3233/JAD-121828 ↗
46. Effects of omega-3 fatty acids on inflammatory markers in cerebrospinal fluid and plasma in Alzheimer’s disease: The OmegAD study10.1159/000218081 ↗
47. Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer’s disease: The OmegAD study10.3233/JAD-132042 ↗
48. Omega-3 supplementation in mild to moderate Alzheimer’s disease: Effects on neuropsychiatric symptoms10.1002/gps.1857 ↗
49. Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer’s disease: The OmegAD study10.1111/joim.12166 ↗
50. Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer’s Disease: The OmegAD Study10.3233/JAD-181148 ↗
51. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: A randomized trial10.1001/jama.2010.1510 ↗
52. Effect of APOE Genotype on Plasma Docosahexaenoic Acid (DHA), Eicosapentaenoic Acid, Arachidonic Acid, and Hippocampal Volume in the Alzheimer’s Disease Cooperative Study-Sponsored DHA Clinical Trial10.3233/JAD-191017 ↗
53. Supplementation With Carotenoids, Omega-3 Fatty Acids, and Vitamin E Has a Positive Effect on the Symptoms and Progression of Alzheimer’s Disease10.3233/JAD-220556 ↗
54. Omega-3 fatty acids and blood-based biomarkers in Alzheimer’s disease and mild cognitive impairment: A randomized placebo-controlled trial10.1016/j.bbi.2021.10.014 ↗
55. The potential role of nutritional components in the management of Alzheimer’s Disease10.1016/j.ejphar.2008.01.049 ↗
56. Nutrients in the Prevention of Alzheimer’s Disease10.1155/2019/9874159 ↗
57. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally10.1016/j.brainres.2006.03.019 ↗
58. Oral administration of circulating precursors for membrane phosphatides can promote the synthesis of new brain synapses
59. Souvenaid for Alzheimer’s disease
60. Efficacy of Souvenaid® Combined with Acetylcholinesterase Inhibitors in the Treatment of Mild Alzheimer’s Disease10.3233/JAD-221003 ↗
61. Exploring effects of Souvenaid on cerebral glucose metabolism in Alzheimer’s disease10.1016/j.trci.2019.08.002 ↗
62. Souvenaid reduces behavioral deficits and improves social cognition skills in frontotemporal dementia: A proof-of-concept study10.1159/000369811 ↗
63. Effects of Souvenaid on plasma micronutrient levels and fatty acid profiles in mild and mild-to-moderate Alzheimer’s disease10.1186/s13195-015-0134-1 ↗
64. Effect of a medical food on body mass index and activities of daily living in patients with Alzheimer’s disease: Secondary analyses from a randomized, controlled trial10.1007/s12603-011-0339-3 ↗
65. Efficacy of a medical food in mild Alzheimer’s disease: A randomized, controlled trial10.1016/j.jalz.2009.10.003 ↗
66. Efficacy of Souvenaid in mild Alzheimer’s disease: Results from a randomized, controlled trial10.3233/JAD-2012-121189 ↗
67. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer’s disease (LipiDiDiet): A randomised, double-blind, controlled trial10.1016/S1474-4422(17)30332-0 ↗
68. The S-Connect study: Results from a randomized, controlled trial of Souvenaid in mild-to-moderate Alzheimer’s disease10.1186/alzrt224 ↗
69. Tolerability and safety of Souvenaid in patients with mild Alzheimer’s disease: Results of multi-center, 24-week, open-label extension study10.3233/JAD-141305 ↗
70. Micronutrient supplementation in mild Alzheimer disease patients10.1016/S0261-5614(03)00106-7 ↗
71. Improvement of weight and fat-free mass with oral nutritional supplementation in patients with Alzheimer’s disease at risk of malnutrition: A prospective randomized study10.1111/j.1532-5415.2004.52464.x ↗
72. Nutrition guidance within a multimodal intervention improves diet quality in prodromal Alzheimer’s disease: Multimodal Preventive Trial for Alzheimer’s Disease (MIND-ADmini)10.1186/s13195-024-01522-8 ↗
73. Naomi, R., Embong, H., Othman, F., Ghazi, H.F., Maruthey, N., and Bahari, H. (2021). Probiotics for Alzheimer’s Disease: A Systematic Review. Nutrients, 14.10.3390/nu14010020 ↗
74. Hsu, Y.C., Huang, Y.Y., Tsai, S.Y., Kuo, Y.W., Lin, J.H., Ho, H.H., Chen, J.F., Hsia, K.C., and Sun, Y. (2023). Efficacy of Probiotic Supplements on Brain-Derived Neurotrophic Factor, Inflammatory Biomarkers, Oxidative Stress and Cognitive Function in Patients with Alzheimer’s Dementia: A 12-Week Randomized, Double-Blind Active-Controlled Study. Nutrients, 16.10.3390/nu16010016 ↗
75. The effects of probiotic supplements on oxidative stress and inflammation in subjects with mild and moderate Alzheimer’s disease: A randomized, double-blind, placebo-controlled study10.1007/s10787-023-01427-2 ↗
76. Probiotic and selenium co-supplementation, and the effects on clinical, metabolic and genetic status in Alzheimer’s disease: A randomized, double-blind, controlled trial10.1016/j.clnu.2018.11.034 ↗
77. The effects of fenugreek seed extract supplementation in patients with Alzheimer’s disease: A randomized, double-blind, placebo-controlled trial10.1002/ptr.7612 ↗
78. Supranutritional Sodium Selenate Supplementation Delivers Selenium to the Central Nervous System: Results from a Randomized Controlled Pilot Trial in Alzheimer’s Disease
79. Positive effects of soy lecithin-derived phosphatidylserine plus phosphatidic acid on memory, cognition, daily functioning, and mood in elderly patients with Alzheimer’s disease and dementia10.1007/s12325-014-0165-1 ↗
80. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease10.1212/WNL.0b013e3182309fa5 ↗
81. Association between malnutrition and hyperhomocysteine in Alzheimer’s disease patients and diet intervention of betaine10.1002/jcla.22090 ↗
82. Passeri, E., Elkhoury, K.M., Morsink, M., Broersen, K., Linder, M., Tamayol, A., Malaplate, C., Yen, F.T., and Arab-Tehrany, E. (2022). Alzheimer’s Disease: Treatment Strategies and Their Limitations. Int. J. Mol. Sci., 23.10.3390/ijms232213954 ↗
83. Efficacy of probiotics on cognition, and biomarkers of inflammation and oxidative stress in adults with Alzheimer’s disease or mild cognitive impairment—A meta-analysis of randomized controlled trials10.18632/aging.102810 ↗
84. Agahi, A., Hamidi, G.A., Daneshvar, R., Hamdieh, M., Soheili, M., Alinaghipour, A., Esmaeili Taba, S.M., and Salami, M. (2018). Does Severity of Alzheimer’s Disease Contribute to Its Responsiveness to Modifying Gut Microbiota? A Double Blind Clinical Trial. Front. Neurol., 9.10.3389/fneur.2018.00662 ↗
85. Role of Vitamins in Neurodegenerative Diseases: A Review10.2174/1871527320666211119122150 ↗
86. Selenium and brain function: A poorly recognized liaison10.1016/j.brainresrev.2004.03.004 ↗