Effect of long-term nutraceutical and dietary supplement use on cognition in the elderly: a 10-year systematic review of randomised controlled trials.

Nutraceuticals have generated interest as a way to mitigate the cognitive decline in older adults. The aim of this systematic review was to determine the evidence for these claims from the scientific literature in randomised, double-blinded, controlled trials (duration: ≥1 year; participants: n≥100; age(mean): ≥65 years). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched four electronic databases (PubMed, Scopus, CINAHL and Web of Science) and identified twenty-five studies published between the 15·June·2006 and 14·June·2016. Interventions included B-vitamins, n-3 fatty acids, antioxidant vitamins and herbs. Of the B-vitamin studies, four found benefits to cognition with supplementation. The first of these B-vitamin studies, in individuals with mild cognitive impairment (n 266; duration=2 years), included benefit to executive function (P=0·015) and improvements in the Mini-Mental State Examination (MMSE) among participants with baseline homocysteine above 11·3 µmol/l (P<0·001). In the same sample, the second study found cognitive benefits of B-vitamins dependent on the higher baseline plasma n-3 fatty acid status. The third B-vitamin study (n 900; duration=2 years) reported improved performance in immediate (P=0·046) and delayed recall (P=0·013), whereas the fourth study (n 856; duration=2 years) reported slower rate of cognitive decline in the MMSE (P=0·05). One study investigating DHA treatment (n 402; duration=1·5 years) revealed the slower rate of cognitive change in apoE e4 non-carriers (P=0·03). As only five included studies revealed notable benefits, presently based on the specific compounds explored here, there is not compelling evidence to support the use nutraceuticals to improve cognition in the elderly. Future long-term trials of nutraceuticals should investigate interactions with lifestyle, blood biomarkers and genetic risk factors.

[1]  E. Georgousopoulou,et al.  The Effects of Green Tea Amino Acid L-Theanine Consumption on the Ability to Manage Stress and Anxiety Levels: a Systematic Review , 2019, Plant Foods for Human Nutrition.

[2]  J. Higgins,et al.  Cochrane Handbook for Systematic Reviews of Interventions , 2010, International Coaching Psychology Review.

[3]  L. Schneider,et al.  Lessons from the Multidomain Alzheimer Preventive Trial , 2017, The Lancet Neurology.

[4]  M. Veysey,et al.  Reduced plasma homocysteine levels in elderly Australians following mandatory folic acid fortification – A comparison of two cross-sectional cohorts , 2017 .

[5]  Kay-Tee Khaw,et al.  Effect of Monthly High-Dose Vitamin D Supplementation on Cardiovascular Disease in the Vitamin D Assessment Study: A Randomized Clinical Trial , 2017, JAMA cardiology.

[6]  Blaine R. Roberts,et al.  The APOE ε4 Allele Is Associated with Lower Selenium Levels in the Brain: Implications for Alzheimer's Disease. , 2017, ACS chemical neuroscience.

[7]  S. Lehéricy,et al.  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 , 2017, The Lancet Neurology.

[8]  S. Ulven,et al.  High-quality fish oil has a more favourable effect than oxidised fish oil on intermediate-density lipoprotein and LDL subclasses: a randomised controlled trial. , 2017, The British journal of nutrition.

[9]  C. Heneghan,et al.  The efficacy of supplementation with the novel medical food, Souvenaid, in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials , 2017, Nutritional neuroscience.

[10]  A. Carvalho,et al.  Low‐Dose Aspirin Use and Cognitive Function in Older Age: A Systematic Review and Meta‐analysis , 2017, Journal of the American Geriatrics Society.

[11]  L. Deldicque,et al.  Potential harmful effects of dietary supplements in sports medicine , 2016, Current opinion in clinical nutrition and metabolic care.

[12]  Ashutosh Kumar Singh,et al.  Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015 , 2016, The Lancet.

[13]  Wolfgang Grisold,et al.  World Brain Day 2016: celebrating brain health in an ageing population , 2016, The Lancet Neurology.

[14]  L. Schneider,et al.  The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease , 2016, Alzheimer's Research & Therapy.

[15]  R. Martins,et al.  Curcumin and cognition: a randomised, placebo-controlled, double-blind study of community-dwelling older adults. , 2016, The British journal of nutrition.

[16]  Kun Hu,et al.  Progression of Dementia Assessed by Temporal Correlations of Physical Activity: Results From a 3.5-Year, Longitudinal Randomized Controlled Trial , 2016, Scientific Reports.

[17]  H. De Steur,et al.  Consumer evaluation of food with nutritional benefits: a systematic review and narrative synthesis , 2016, International journal of food sciences and nutrition.

[18]  Jocelyn R. Wilder,et al.  Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011. , 2016, JAMA internal medicine.

[19]  A. Minihane Impact of Genotype on EPA and DHA Status and Responsiveness to Increased Intakes , 2016, Nutrients.

[20]  H. Soininen,et al.  A clinical trial investigating the effects of fortasyn connect (souvenaid) in prodromal Alzheimer’s disease: results of the LipiDiDiet study , 2016, Neurobiology of Aging.

[21]  M. Cesari,et al.  Nutrition and Dementia: Evidence for Preventive Approaches? , 2016, Nutrients.

[22]  Todd M. Solomon,et al.  A randomized, double‐blind, placebo controlled, parallel group, efficacy study of alpha BRAIN® administered orally , 2016, Human psychopharmacology.

[23]  N. Sattar,et al.  Maternal Plasma DHA Levels Increase Prior to 29 Days Post-LH Surge in Women Undergoing Frozen Embryo Transfer: A Prospective, Observational Study of Human Pregnancy. , 2016, The Journal of clinical endocrinology and metabolism.

[24]  D. Kennedy B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review , 2016, Nutrients.

[25]  A. Smith,et al.  Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment , 2016, Journal of Alzheimer's disease : JAD.

[26]  James B. Brewer,et al.  A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease , 2015, Neurology.

[27]  Nadine Shehab,et al.  Emergency Department Visits for Adverse Events Related to Dietary Supplements. , 2015, New England Journal of Medicine.

[28]  Sterling C. Johnson,et al.  Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle-Aged Adults at Risk for Alzheimer Disease. , 2015, JAMA neurology.

[29]  F. Grodstein,et al.  Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. , 2015, JAMA.

[30]  Teng Jiang,et al.  Meta-analysis of modifiable risk factors for Alzheimer's disease , 2015, Journal of Neurology, Neurosurgery & Psychiatry.

[31]  R. Uauy,et al.  Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial , 2015, The American journal of clinical nutrition.

[32]  Lars Bäckman,et al.  A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial , 2015, The Lancet.

[33]  Annemien Haveman-Nies,et al.  Dietary patterns, cognitive decline, and dementia: a systematic review. , 2015, Advances in nutrition.

[34]  W. Maier,et al.  Epidemiological and economic burden of Alzheimer's disease: a systematic literature review of data across Europe and the United States of America. , 2014, Journal of Alzheimer's disease : JAD.

[35]  A. Uitterlinden,et al.  Results of 2-year vitamin B treatment on cognitive performance , 2014, Neurology.

[36]  H. Shirzad,et al.  New Concepts in Nutraceuticals as Alternative for Pharmaceuticals , 2014, International journal of preventive medicine.

[37]  A. Feizi,et al.  The effect of antioxidant vitamins E and C on cognitive performance of the elderly with mild cognitive impairment in Isfahan, Iran: a double-blind, randomized, placebo-controlled trial , 2014, European Journal of Nutrition.

[38]  B. Schwartz New criteria for supplementation of selected micronutrients in the era of nutrigenetics and nutrigenomics , 2014, International journal of food sciences and nutrition.

[39]  R. Collins,et al.  Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals , 2014, The American journal of clinical nutrition.

[40]  S. Jamshed,et al.  Role of complementary and alternative medicine in geriatric care: A mini review , 2014, Pharmacognosy reviews.

[41]  M. Veysey,et al.  Diet and Our Genetic Legacy in the Recent Anthropocene , 2014, Journal of evidence-based complementary & alternative medicine.

[42]  J. Manson,et al.  Long-Term Multivitamin Supplementation and Cognitive Function in Men , 2013, Annals of Internal Medicine.

[43]  Jennifer S. Lin,et al.  Vitamin and Mineral Supplements in the Primary Prevention of Cardiovascular Disease and Cancer: An Updated Systematic Evidence Review for the U.S. Preventive Services Task Force , 2013, Annals of Internal Medicine.

[44]  L. Appel,et al.  Enough Is Enough: Stop Wasting Money on Vitamin and Mineral Supplements , 2013, Annals of Internal Medicine.

[45]  M. Touvier,et al.  Sociodemographic, lifestyle and dietary correlates of dietary supplement use in a large sample of French adults: results from the NutriNet-Santé cohort study. , 2013, The British journal of nutrition.

[46]  M. Lambert,et al.  Nutritional supplement products: does the label information influence purchasing decisions for the physically active? , 2013, Nutrition Journal.

[47]  C. Gluud,et al.  Antioxidant supplements to prevent mortality. , 2013, JAMA.

[48]  D. Panagiotakos A Mediterranean diet supplemented with olive oil or nuts reduces the incidence of major cardiovascular events in high-risk patients , 2013, Evidence-Based Medicine.

[49]  K. Barnes,et al.  Absorption of Marine vs Non‐Marine sources of EPA and DHA , 2013 .

[50]  J. Martínez,et al.  Virgin olive oil supplementation and long-term cognition: the Predimed-Navarra randomized, trial , 2013, The journal of nutrition, health & aging.

[51]  Huaxi Xu,et al.  Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy , 2013, Nature Reviews Neurology.

[52]  A. Pipingas,et al.  Multivitamin-multimineral supplementation and mortality: a meta-analysis of randomized controlled trials. , 2013, American Journal of Clinical Nutrition.

[53]  J. Manson,et al.  Calcium and Vitamin D Supplementation and Cognitive Impairment in the Women's Health Initiative , 2012, Journal of the American Geriatrics Society.

[54]  B. Dubois,et al.  Long-term use of standardised ginkgo biloba extract for the prevention of Alzheimer's disease (GuidAge): a randomised placebo-controlled trial , 2012, The Lancet Neurology.

[55]  R. Heuberger Polypharmacy and Food–Drug Interactions Among Older Persons: A Review , 2012, Journal of nutrition in gerontology and geriatrics.

[56]  J. Opara Activities of daily living and quality of life in Alzheimer disease , 2012, Journal of medicine and life.

[57]  A. Smith,et al.  Cognitive and clinical outcomes of homocysteine‐lowering B‐vitamin treatment in mild cognitive impairment: a randomized controlled trial , 2012, International journal of geriatric psychiatry.

[58]  R. Kaaks,et al.  Vitamin/mineral supplementation and cancer, cardiovascular, and all-cause mortality in a German prospective cohort (EPIC-Heidelberg) , 2012, European Journal of Nutrition.

[59]  U. Raychaudhuri,et al.  Role of nutraceuticals in human health , 2012, Journal of Food Science and Technology.

[60]  C. Reitz Alzheimer's Disease and the Amyloid Cascade Hypothesis: A Critical Review , 2012, International journal of Alzheimer's disease.

[61]  J M Starr,et al.  APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921 , 2012, Molecular Psychiatry.

[62]  Janine G. Walker,et al.  Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms--the Beyond Ageing Project: a randomized controlled trial. , 2011, The American journal of clinical nutrition.

[63]  D. Jacobs,et al.  Dietary supplements and mortality rate in older women: the Iowa Women's Health Study. , 2011, Archives of internal medicine.

[64]  J. Geleijnse,et al.  Effects of n-3 fatty acids on cognitive decline: A randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients , 2011, Alzheimer's & Dementia.

[65]  F. Schmitt,et al.  Vitamin E and all-cause mortality: a meta-analysis. , 2011, Current aging science.

[66]  Jenny Lee,et al.  A randomized placebo controlled trial of homocysteine lowering to reduce cognitive decline in older demented people. , 2011, Clinical nutrition.

[67]  M. McDowell,et al.  Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994). , 2011, NCHS data brief.

[68]  A. Petróczi,et al.  Mission impossible? Regulatory and enforcement issues to ensure safety of dietary supplements. , 2011, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[69]  Michael Weiner,et al.  Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. , 2010, JAMA.

[70]  R. Clarnette,et al.  Vitamins B12, B6, and folic acid for cognition in older men , 2010, Neurology.

[71]  Abderrahim Oulhaj,et al.  Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial , 2010, PloS one.

[72]  Marcus Richards,et al.  Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. , 2010, The American journal of clinical nutrition.

[73]  S. Willich,et al.  Effects of Ginkgo biloba in dementia: systematic review and meta-analysis , 2010, BMC geriatrics.

[74]  K. Sink,et al.  Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. , 2009, JAMA.

[75]  W. Chan,et al.  Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease , 2009, Alzheimers Res Ther.

[76]  K. Mori,et al.  Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double‐blind placebo‐controlled clinical trial , 2009, Phytotherapy research : PTR.

[77]  Lewis H Kuller,et al.  Ginkgo biloba for prevention of dementia: a randomized controlled trial. , 2008, JAMA.

[78]  Ramon Diaz-Arrastia,et al.  High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. , 2008, JAMA.

[79]  R. Bartha,et al.  Ventricular enlargement as a possible measure of Alzheimer's disease progression validated using the Alzheimer's disease neuroimaging initiative database. , 2008, Brain : a journal of neurology.

[80]  K. Meguro,et al.  Comprehensive approach of donepezil and psychosocial interventions on cognitive function and quality of life for Alzheimer's disease: the Osaki-Tajiri Project. , 2008, Age and ageing.

[81]  Dick F Swaab,et al.  Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. , 2008, JAMA.

[82]  J. Kaye,et al.  A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline , 2008, Neurology.

[83]  Stian Lydersen,et al.  APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway , 2008, BMC neurology.

[84]  V. Mok,et al.  Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. , 2008, Journal of clinical psychopharmacology.

[85]  J. Palmblad,et al.  Omega‐3 supplementation in mild to moderate Alzheimer's disease: effects on neuropsychiatric symptoms , 2008, International journal of geriatric psychiatry.

[86]  N. Cook,et al.  A randomized trial of beta carotene supplementation and cognitive function in men: the Physicians' Health Study II. , 2007, Archives of internal medicine.

[87]  A. Avenell,et al.  Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial , 2007, Nutrition journal.

[88]  Petra Verhoef,et al.  Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial , 2007, The Lancet.

[89]  Lars-Olof Wahlund,et al.  Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. , 2006, Archives of neurology.

[90]  J. Mann,et al.  A controlled trial of homocysteine lowering and cognitive performance. , 2006, The New England journal of medicine.

[91]  J. K. Djernes,et al.  Prevalence and predictors of depression in populations of elderly: a review , 2006, Acta psychiatrica Scandinavica.

[92]  G. McDougall,et al.  Utility of Nutraceutical Products Marketed for Cognitive and Memory Enhancement , 2005, Journal of holistic nursing : official journal of the American Holistic Nurses' Association.

[93]  Mark Lucock,et al.  Folic acid — vitamin and panacea or genetic time bomb? , 2005, Nature Reviews Genetics.

[94]  J. Hathcock Dietary supplements: how they are used and regulated. , 2001, The Journal of nutrition.

[95]  T. Byers What can randomized controlled trials tell us about nutrition and cancer prevention? , 1999, CA: a cancer journal for clinicians.

[96]  M. Traber,et al.  Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. , 1998, The American journal of clinical nutrition.

[97]  J. Haines,et al.  Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. , 1997, JAMA.

[98]  J. Haines,et al.  Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis , 1997 .

[99]  J Carter,et al.  Molecular Pathology of Alzheimer's Disease , 2013 .

[100]  C. Rowe,et al.  Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts. , 2014, Journal of Alzheimer's disease : JAD.

[101]  T. Tholstrup Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline , 2012 .

[102]  Australian Public Assessment Report for Melatonin Proprietary Product , 2011 .

[103]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[104]  E. Kalra Nutraceutical-definition and introduction , 2008, AAPS PharmSci.

[105]  E. Yetley Multivitamin and multimineral dietary supplements: definitions, characterization, bioavailability, and drug interactions. , 2007, The American journal of clinical nutrition.

[106]  Deborah Gustafson,et al.  Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. , 2004, Archives of neurology.