Previous studies have indicated that B vitamin deficiencies are an essential cause of neurological pathology. There is a need to provide evidence of the benefit of B vitamins for the prevention of cognitive decline in community-dwelling older adults.
Objective:
To examine the association between intake and plasma levels of vitamins B12, B6, and folate and cognitive function in older populations through a systematic review and meta-analysis.
Methods:
Medline (PubMed), EMBASE, and Cochrane databases were used to search the literature though August 8, 2019. We included observational population-based studies evaluating the association between concentrations or intake levels of vitamins B6, B12, or folate and cognition in older adults aged ≥45 years. The quality of all studies was assessed by the modified Newcastle-Ottawa Scale. Odds ratios (ORs) and hazard ratios (HRs) were analyzed by the random-effects model. Sensitivity analyses were conducted by excluding the studies with significant heterogeneity.
Results:
Twenty-one observational studies with sample sizes ranging from 155–7030 were included in the meta-analysis. Higher levels of vitamin B12 (OR = 0.77, 95% CI = 0.61–0.97) and folate concentration (OR = 0.68, 95% CI = 0.51–0.90) were associated with better cognition in cross-sectional studies, but not in sensitivity analyses or prospective studies. High vitamin B6 concentrations showed no significant benefit on cognition and dementia risk. Prospective studies did not provide substantial evidence for the relationship.
Conclusion:
The results from our meta-analysis suggest that vitamins B12, B6, and folate may not be modifiable risk factors for slowing cognitive decline among community-dwelling older individuals.
JackCJ, KnopmanDS, JagustWJ, PetersenRC, WeinerMW, AisenPS, ShawLM, VemuriP, WisteHJ, WeigandSD, LesnickTG, PankratzVS, DonohueMC, TrojanowskiJQ (2013) Tracking pathophysiological processes in Alzheimer’s disease: An updated hypothetical model of dynamic biomarkers. Lancet Neurol12, 207–216.
2.
RegeSD, GeethaT, BroderickTL, BabuJR (2017) Can diet and physical activity limit Alzheimer’s disease risk?Curr Alzheimer Res14, 76–93.
3.
MontiJM, MoultonCJ, CohenNJ (2015) The role of nutrition on cognition and brain health in ageing: A targeted approach. Nutr Res Rev28, 167–180.
4.
GustafsonDR, ClareMM, ScarmeasN, ShahRC, SijbenJ, YaffeK, ZhuX (2015) New perspectives on Alzheimer’s disease and nutrition. J Alzheimers Dis46, 1111–1127.
5.
Gillette-GuyonnetS, SecherM, VellasB (2013) Nutrition and neurodegeneration: Epidemiological evidence and challenges for future research. Br J Clin Pharmacol75, 738–755.
6.
FerryM, ColeyN, AndrieuS, BonhommeC, CaubereJP, CesariM, GautryJ, GarciaSI, HugonotL, MansuyL, PahorM, ParienteJ, RitzP, SalvaA, SijbenJ, WieggersR, Ythier-MouryP, ZaimM, ZetlaouiJ, VellasB (2013) How to design nutritional intervention trials to slow cognitive decline in apparently healthy populations and apply for efficacy claims: A statement from the International Academy on Nutrition and Aging Task Force. J Nutr Health Aging17, 619–623.
7.
XuW, WuC (2018) Detecting spatiotemporal clusters of dementia mortality in the United States, 2000-2010. Spat Spatiotemporal Epidemiol27, 11–20.
8.
APA Work Group on Alzheimer’s Disease and other Dementias, RabinsPV, BlackerD, RovnerBW, RummansT, SchneiderLS, TariotPN, BlassDM; Steering Committee on Practice Guidelines, McIntyreJS, CharlesSC, AnziaDJ, CookIA, FinnertyMT, JohnsonBR, NiningerJE, SchneidmanB, SummergradP, WoodsSM, BergerJ, CrossCD, BrandtHA, MargolisPM, ShemoJP, BlinderBJ, DuncanDL, BarnovitzMA, CarinoAJ, FreybergZZ, GraySH, TonnuT, KunkleR, AlbertAB, CraigTJ, RegierDA, FochtmannLJ (2007) American Psychiatric Association practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. Second edition. Am J Psychiatry164(12 Suppl), 5–56.
9.
AgroninM (2014) Alzheimer’s Disease and Other Dementias: A Practical Guide, Routledge, New York.
.
10.
FordAH, AlmeidaOP (2019) Effect of vitamin B supplementation on cognitive function in the elderly: A systematic review and meta-analysis. }. Drugs Aging36, 419–434.
11.
CaoL, TanL, WangH, JiangT, ZhuX, LuH, TanM, YuJ (2016) Dietary patterns and risk of dementia: A systematic review and meta-analysis of cohort studies. Mol Neurobiol53, 6144–6154.
12.
JiaX, McNeillG, AvenellA (2008) Does taking vitamin, mineral and fatty acid supplements prevent cognitive decline? A systematic review of randomized controlled trials. J Hum Nutr Diet21, 317–336.
13.
MoherD, LiberatiA, TetzlaffJ, AltmanDG; PRISMA Group (2009) Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med6, e1000097.
14.
RajasekharA, LottenbergR, LottenbergL, LiuH, AngD (2011) Pulmonary embolism prophylaxis with inferior vena cava filters in trauma patients: A systematic review using the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. J Thromb Thrombolysis32, 40–46.
15.
AnnweilerC, Montero-OdassoM, LlewellynDJ, Richard-DevantoyS, DuqueG, BeauchetO (2013) Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis37, 147–171.
16.
FellerM, SnelM, MoutzouriE, BauerDC, de MontmollinM, AujeskyD, FordI, GusseklooJ, KearneyPM, MooijaartS, QuinnT, StottD, WestendorpR, RodondiN, DekkersOM (2018) Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism. JAMA320, 1349.
17.
MendoncaN, GranicA, MathersJC, Martin-RuizC, WesnesKA, SealCJ, JaggerC, HillTR (2017) One-carbon metabolism biomarkers and cognitive decline in the very old: The newcastle 85+study. J Am Med Dir Assoc18, 806.e19–806.e27.
18.
MaxwellCJ, HoganDB, EblyEM (2002) Serum folate levels and subsequent adverse cerebrovascular outcomes in elderly persons. Dement Geriatr Cogn Disord13, 225–234.
19.
PalaciosN, ScottT, SahasrabudheN, GaoX, TuckerKL (2019) Lower plasma vitamin B-6 is associated with 2-year cognitive decline in the Boston Puerto Rican health study. J Nutr149, 635–641.
20.
NelsonC, WengreenHJ, MungerRG, CorcoranCD (2009) Dietary folate, vitamin B-12, vitamin B-6 and incident Alzheimer’s disease: The cache county memory, health and aging study. J Nutr Health Aging13, 899–905.
21.
VercambreMN, Boutron-RuaultMC, RitchieK, Clavel-ChapelonF, BerrC (2009) Long-term association of food and nutrient intakes with cognitive and functional decline: A 13-year follow-up study of elderly French women. Br J Nutr102, 419–427.
22.
LuchsingerJA, TangMX, MillerJ, GreenR, MayeuxR (2007) Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch Neurol64, 86–92.
23.
Agnew-BlaisJC, Wassertheil-SmollerS, KangJH, HoganPE, CokerLH, SnetselaarLG, SmollerJW (2015) Folate, vitamin B-6, and vitamin B-12 intake and mild cognitive impairment and probable dementia in the Women’s Health Initiative Memory Study. J Acad Nutr Diet115, 231–241.
24.
FischerP, ZehetmayerS, JungwirthS, WeissgramS, KramplaW, HinterbergerM, TormaS, RainerM, HuberK, HoenigschnablS, GelpiE, BauerK, LeithaT, BauerP, TraglKH (2008) Risk factors for Alzheimer dementia in a community-based birth cohort at the age of 75 years. Dement Geriatr Cogn Disord25, 501–507.
25.
KadoDM, KarlamanglaAS, HuangMH, TroenA, RoweJW, SelhubJ, SeemanTE (2005) Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med118, 161–167.
26.
Castillo-LancellottiC, MargozziniP, ValdiviaG, PadillaO, UauyR, RozowskiJ, TurJA (2015) Serum folate, vitamin B12 and cognitive impairment in Chilean older adults. Public Health Nutr18, 2600–2608.
27.
RamosMI, AllenLH, MungasDM, JagustWJ, HaanMN, GreenR, MillerJW (2005) Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr82, 1346–1352.
28.
HughesCF, WardM, TraceyF, HoeyL, MolloyAM, PentievaK, McNultyH (2017) B-vitamin intake and biomarker status in relation to cognitive decline in healthy older adults in a 4-year follow-up study. Nutrients9, 53.
29.
LildballeDL, FedosovS, SherlikerP, HinH, ClarkeR, NexoE (2011) Association of cognitive impairment with combinations of vitamin B(1)(2)-related parameters. Clin Chem57, 1436–1443.
30.
ClarkeR, SherlikerP, HinH, MolloyAM, NexoE, UelandPM, EmmensK, ScottJM, EvansJG (2008) Folate and vitamin B12 status in relation to cognitive impairment and anaemia in the setting of voluntary fortification in the UK. Br J Nutr100, 1054–1059.
31.
WangHX, WahlinA, BasunH, FastbomJ, WinbladB, FratiglioniL (2001) Vitamin B(12) and folate in relation to the development of Alzheimer’s disease. Neurology56, 1188–1194.
32.
HooshmandB, SolomonA, KareholtI, RusanenM, HanninenT, LeiviskaJ, WinbladB, LaatikainenT, SoininenH, KivipeltoM (2012) Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: A longitudinal study. J Intern Med271, 204–212.
33.
BrownB, HuangMH, KarlamanglaA, SeemanT, KadoD (2011) Do the effects of APOE-epsilon4 on cognitive function and decline depend upon vitamin status? MacArthur Studies of Successful Aging. J Nutr Health Aging15, 196–201.
34.
HinH, ClarkeR, SherlikerP, AtoyebiW, EmmensK, BirksJ, SchneedeJ, UelandPM, NexoE, ScottJ, MolloyA, DonaghyM, FrostC, EvansJG (2006) Clinical relevance of low serum vitamin B12 concentrations in older people: The Banbury B12 study. Age Ageing35, 416–422.
35.
KimS, ChoiBY, NamJH, KimMK, OhDH, YangYJ (2019) Cognitive impairment is associated with elevated serum homocysteine levels among older adults. Eur J Nutr58, 399–408.
36.
Lefevre-ArbogastS, FeartC, DartiguesJF, HelmerC, LetenneurL, SamieriC (2016) Dietary B vitamins and a 10-year risk of dementia in older persons. Nutrients8, 761.
37.
MorrisMC, EvansDA, SchneiderJA, TangneyCC, BieniasJL, AggarwalNT (2006) Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer’s disease. J Alzheimers Dis9, 435–443.
38.
SechiG, SechiE, FoisC, KumarN (2016) Advances in clinical determinants and neurological manifestations of B vitamin deficiency in adults. Nutr Rev74, 281–300.
39.
ClarkeR, BirksJ, NexoE, UelandPM, SchneedeJ, ScottJ, MolloyA, EvansJG (2007) Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr86, 1384–1391.
40.
DaviglusML, PlassmanBL, PirzadaA, BellCC, BowenPE, BurkeJR, ConnollyEJ, Dunbar-JacobJM, GranieriEC, McGarryK, PatelD, TrevisanM, WilliamsJJ (2011) Risk factors and preventive interventions for Alzheimer disease: State of the science. Arch Neurol68, 1185–1190.
41.
den ElzenWP, van der WeeleGM, GusseklooJ, WestendorpRG, AssendelftWJ (2010) Subnormal vitamin B12 concentrations and anaemia in older people: A systematic review. BMC Geriatr10, 42.
42.
DangourAD, AllenE, ClarkeR, ElbourneD, FaseyN, FletcherAE, LetleyL, RichardsM, WhyteK, MillsK, UauyR (2011) A randomised controlled trial investigating the effect of vitamin B12 supplementation on neurological function in healthy older people: The Older People and Enhanced Neurological function (OPEN) study protocol [ISRCTN54195799]. Nutr J10, 22.
43.
SeemanTE, HuangM, BretskyP, CrimminsE, LaunerL, GuralnikJM (2005) Education and APOE-e4 in longitudinal cognitive decline: MacArthur Studies of Successful Aging. , P74-P. J Gerontol B Psychol Sci Soc Sci60, 83.
44.
SilvaD, AlbersU, SantanaI, VicenteM, MartinsIP, VerdelhoA, GuerreiroM, De-MendoncaA (2013) Do MCI patients with vitamin B12 deficiency have distinctive cognitive deficits? . BMC Res Notes6, 357.
CorradaMM, KawasCH, HallfrischJ, MullerD, BrookmeyerR (2005) Reduced risk of Alzheimer’s disease with high folate intake: The Baltimore Longitudinal Study of Aging. Alzheimers Dement1, 11–18.
47.
CarneyE, CanadaT (2006) Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Nutr Clin Pract21, 188–189.
48.
DoetsEL, UelandPM, TellGS, VollsetSE, NygardOK, Van’TVP, De GrootLCPG, NurkE, RefsumH, SmithAD, EussenSJPM (2014) Interactions between plasma concentrations of folate and markers of vitamin B12 status with cognitive performance in elderly people not exposed to folic acid fortification: The Hordaland Health Study. Br J Nutr111, 1085–1095.
49.
ClarkeR, BennettD, ParishS, LewingtonS, SkeaffM, EussenSJ, LewerinC, StottDJ, ArmitageJ, HankeyGJ, LonnE, SpenceJD, GalanP, de GrootLC, HalseyJ, DangourAD, CollinsR, GrodsteinF (2014) Effects of homocysteine lowering with B vitamins on cognitive aging: Meta-analysis of 11 trials with cognitive data on 22,000 individuals. Am J Clin Nutr100, 657–666.
50.
DurgaJ, van BoxtelMP, SchoutenEG, KokFJ, JollesJ, KatanMB, VerhoefP (2007) Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: A randomised, double blind, controlled trial. Lancet369, 208–216.
51.
WaldDS, KasturiratneA, SimmondsM (2010) Effect of folic acid, with or without other B vitamins, on cognitive decline: Meta-analysis of randomized trials. Am J Med123, 522–527.e2.
52.
KirkseyA, MorréDM, WasynczukAZ (1990) Neuronal development in vitamin B6 deficiency. Ann N Y Acad Sci585, 202–218.
53.
EricksonKI, SueverBL, PrakashRS, ColcombeSJ, McAuleyE, KramerAF (2008) Greater intake of vitamins B6 and B12 spares gray matter in healthy elderly: A voxel-based morphometry study. Brain Res1199, 20–26.
54.
KarlssonI (1993) Neurotransmitter changes in aging and dementia. Nord J Psychiatry47, 41–44.
55.
JannuschK, JockwitzC, BidmonH, MoebusS, AmuntsK, CaspersS (2017) A complex interplay of vitamin B1 and B6 metabolism with cognition, brain structure, and functional connectivity in older adults. Front Neurosci11, 596.
56.
SmithA, SmithS, de JagerC, WhitbreadP, JohnstonC, AgacinskiG, OulhajA, BradleyK, JacobyR, RefsumH (2010) Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: A randomized controlled trial. PLoS One5, e12244.
57.
de van der SchuerenMAE, Lonterman-MonaschS, van der Flier WM, KramerMH, MaierAB, MullerM (2016) Malnutrition and risk of structural brain changes seen on magnetic resonance imaging in older adults. J Am Geriatr Soc64, 2457–2463.
58.
HarrisE, MacphersonH, PipingasA (2015) Improved blood biomarkers but no cognitive effects from 16 weeks of multivitamin supplementation in healthy older adults. Nutrients7, 3796–3812.
59.
FordAH, FlickerL, HankeyGJ, NormanP, van BockxmeerFM, AlmeidaOP (2012) Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and cognitive impairment: The health in men study. Mol Psychiatry17, 559–566.
60.
SmithAD (2008) The worldwide challenge of the dementias: A role for B vitamins and homocysteine?Food Nutr Bull29, S143–S172.
61.
Van DamF, Van GoolA (2009) Hyperhomocysteinemia and Alzheimer’s disease: A systematic review. Arch Gerontol Geriatr48, 425–430.
62.
ParkinsKJ, PoetsCF, O’BrienLM, StebbensVA, SouthallDP (1998) Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ316, 894–898.
63.
ClaytonPT (2006) B6-responsive disorders: A model of vitamin dependency. J Inherit Metab Dis29, 317–326.
64.
LucockM, YatesZ (2002) Measurement of red blood cell methylfolate. Lancet360, 1021–1022.
65.
CarmelR (2011) Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: A critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II. Am J Clin Nutr94, 348S–358S.
66.
HeilSG, de JongeR, de RotteMCFJ, van WijnenM, Heiner-FokkemaRMR, KoboldACM, PekelharingJMM, AdriaansenHJ, SandersE, TrienekensPH, RammelooT, LindemansJ (2012) Screening for metabolic vitamin B12 deficiency by holotranscobalamin in patients suspected of vitamin B12 deficiency: A multicentre study. Ann Clin Biochem49, 184–189.
67.
de JagerCA, OulhajA, JacobyR, RefsumH, SmithAD (2012) Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: A randomized controlled trial. Int J Geriatr Psychiatry27, 592–600.
68.
MaloufR, Grimley EvansJ (2008) Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev4, CD004514.
69.
BlountBC, MackMM, WehrCM, MacGregorJT, HiattRA, WangG, WickramasingheSN, EversonRB, AmesBN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proc Natl Acad Sci U S A94, 3290–3295.
70.
MorrisMC, EvansDA, BieniasJL, ScherrPA, TangneyCC, HebertLE, BennettDA, WilsonRS, AggarwalN (2004) Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J Neurol Neurosurg Psychiatry75, 1093–1099.
