Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals

Robert Clarke¹, Derrick Bennett¹, Sarah Parish¹, Sarah Lewington¹, Murray Skeaff¹, Simone J P M Eussen¹, Catharina Lewerin¹, David J Stott¹, Jane Armitage¹, Graeme J Hankey¹, Eva Lonn¹, J David Spence¹, Pilar Galan¹, Lisette C de Groot¹, Jim Halsey¹, Alan D Dangour¹, Rory Collins¹, Francine Grodstein¹; B-Vitamin Treatment Trialists’ Collaboration

Affiliations

Affiliation

¹ From the Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, United Kingdom (R Clarke, DB, SP, SL, JA, JH, and R Collins); the Department of Human Nutrition, University of Otago, Dunedin, New Zealand (MS); the Section for Pharmacology and Department of Public Health and Primary Care, University of Bergen, Bergen, Norway (SJPME); the Department of Epidemiology, School for Public Health and Primary Care, CAPHRI, Maastricht University Medical Centre, Maastricht, Netherlands (SJPME); the Section of Hematology and Coagulation, Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden (CL); the Division of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom (DJS); the School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia (GJH); the Population Health Research Institute and Department of Medicine, McMaster University, Hamilton, Canada (EL); the Department of Neurology, Western University, London, Canada (JDS); Unité de Recherche en Epidémiologie Nutritonnelle (UREN), Sorbonne-Paris-Cité, UMR Inserm U557, France (PG); Inra U1125, Paris, France (PG); Cnam, Paris, France (PG); Université Paris 13, CRNH IdF, Bobigny, France (PG); the Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, Netherlands (LCdG); the Department of Nutrition and Public Health Intervention Research, London School of Hygiene and Tropical Medicine, London, United Kingdom (ADD); and the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA (FG).

PMID: 24965307
PMCID: PMC4095663
DOI: 10.3945/ajcn.113.076349

Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals

Robert Clarke et al. Am J Clin Nutr. 2014 Aug.

. 2014 Aug;100(2):657-66.

doi: 10.3945/ajcn.113.076349. Epub 2014 Jun 25.

Authors

Affiliation

¹ From the Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, United Kingdom (R Clarke, DB, SP, SL, JA, JH, and R Collins); the Department of Human Nutrition, University of Otago, Dunedin, New Zealand (MS); the Section for Pharmacology and Department of Public Health and Primary Care, University of Bergen, Bergen, Norway (SJPME); the Department of Epidemiology, School for Public Health and Primary Care, CAPHRI, Maastricht University Medical Centre, Maastricht, Netherlands (SJPME); the Section of Hematology and Coagulation, Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden (CL); the Division of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom (DJS); the School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia (GJH); the Population Health Research Institute and Department of Medicine, McMaster University, Hamilton, Canada (EL); the Department of Neurology, Western University, London, Canada (JDS); Unité de Recherche en Epidémiologie Nutritonnelle (UREN), Sorbonne-Paris-Cité, UMR Inserm U557, France (PG); Inra U1125, Paris, France (PG); Cnam, Paris, France (PG); Université Paris 13, CRNH IdF, Bobigny, France (PG); the Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, Netherlands (LCdG); the Department of Nutrition and Public Health Intervention Research, London School of Hygiene and Tropical Medicine, London, United Kingdom (ADD); and the Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA (FG).

PMID: 24965307
PMCID: PMC4095663
DOI: 10.3945/ajcn.113.076349

Abstract

Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain.

Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging.

Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)-type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals).

Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: -0.054 ± 0.004 and -0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: -0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: -0.01; 95% CI: -0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: -0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment.

Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.

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Figures

**FIGURE 1.**
Effects of B vitamins on specific domains of cognitive function and on a domain-composite score by using change from baseline in the cognitive-domain trials. The z scores for individual trials and the total for the cognitive-domain trials are shown separately for memory, speed, and executive function and for a domain-composite global cognitive function score. Black squares represent z score differences for the individual trials and the horizontal lines represent 95% CIs. The size of the squares is inversely proportional to the variance. Diamonds represent the z scores and 95% CIs for all trials.

**FIGURE 2.**
Effects of B vitamins on MMSE-type global cognitive function score at the end of the treatment period in the global cognition trials. The z score for differences and their 95% CIs for MMSE-type global cognitive function scores are shown for individual trials and as the total for all trials. The z score differences are for B-vitamins compared with placebo. * refers to B-vitamin based treatment vs placebo. HOPE-2, Heart Outcomes Prevention Evaluation-2; MMSE, Mini-Mental State Examination; SEARCH, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; SU.FOL.OM3, Supplementation with Folate, vitamin B6 and B12 and/or Omega-3 fatty acids; VISP, Vitamin Intervention for Stroke Prevention; VITATOPS, Vitamins to Prevent Stroke; WAFACS, Women's Antioxidant and Folic Acid Cardiovascular Study.

**FIGURE 3.**
Effects of B vitamins on cognitive aging in all available trials per year at a 25% reduction in homocysteine. The z score differences and their 95% CIs are provided for the domain-composite global cognitive function score in each cognitive-domain trial and for the MMSE-type global cognitive function score in the other trials. The years of cognitive aging equivalent and their 95% CIs are also provided for individual trials and their totals. The years of cognitive aging equivalent were determined on the basis of a 0.054/y reduction in the cognitive domain trial score and a 0.036/y reduction in the global cognition trial score. * indicates that the age association was based on 0.054 per year reduction in domain-composite z score for cognitive-domain trials and on 0.036 per year reduction in MMSE-type cognitive z score. FACIT, Folic Acid and Carotid Intima-Media Thickness; HOPE-2, Heart Outcomes Prevention Evaluation-2; MMSE, Mini-Mental State Examination; SEARCH, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine; SU.FOL.OM3, Supplementation with Folate, vitamin B6 and B12 and/or Omega-3 fatty acids; tHcy, total homocysteine; VISP, Vitamin Intervention for Stroke Prevention; VITATOPS, Vitamins to Prevent Stroke; WAFACS, Women's Antioxidant and Folic Acid Cardiovascular Study.

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Comment in

B-vitamin trials meta-analysis: less than meets the eye.
Garrard P, Jacoby R. Garrard P, et al. Am J Clin Nutr. 2015 Feb;101(2):414-5. doi: 10.3945/ajcn.114.097808. Am J Clin Nutr. 2015. PMID: 25646342 No abstract available.
Homocysteine lowering, B vitamins, and cognitive aging.
Smith AD, de Jager CA, Refsum H, Rosenberg IH. Smith AD, et al. Am J Clin Nutr. 2015 Feb;101(2):415-6. doi: 10.3945/ajcn.114.098467. Am J Clin Nutr. 2015. PMID: 25646343 No abstract available.
Reply to Garrard and Jacoby and Smith et al.
Clarke R, Bennett D, Parish S; B-Vitamin Treatment Trialists’ Collaboration. Clarke R, et al. Am J Clin Nutr. 2015 Feb;101(2):416-7. doi: 10.3945/ajcn.114.100941. Am J Clin Nutr. 2015. PMID: 25646344 No abstract available.

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Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals

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Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals

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