Alzheimer’s disease (AD) is the main cause of sporadic dementia in the elderly Citation[1]. There are no known curative or preventive measures for AD, and delaying the onset could decrease its prevalence and public health burden Citation[2]. Thus, there have been extensive research efforts in identifying risk factors for AD. The risk of sporadic AD increases with age. It is also higher in individuals with lower education. The only robust genetic risk factor for AD is the APOE-ε4 allele Citation[3]. Vascular risk factors and cerebrovascular disease are increasingly recognized as potential risk factors for AD Citation[4]. The main culprit in AD is thought to be the deposition of amyloid-β in the brain Citation[5], leading to loss of synapses and neuronal destruction. Thus, it is thought that dietary factors that affect AD risk are those that have an effect on the amyloid cascade. Another potentially important mechanism linking diet and AD is cardiovascular and cerebrovascular disease Citation[6].
Homocysteine has surfaced as a potential risk factor for cardiovascular disease and dementia Citation[7]. Homocysteine levels in the blood are largely determined by dietary intake and levels of folate, and vitamins B6 and B12 Citation[8], but increase with age and diminishing renal function Citation[9]. Homocysteine is a precursor of methionine and cysteine. Folate and vitamin B12 are needed for the conversion of homocysteine to methionine and vitamin B6 is needed for the conversion of homocysteine to cysteine. Homocysteine can act in the brain and possibly in the AD pathway through vascular mechanisms or as a neurotoxin Citation[10], but the mechanisms are not clear. Lower serum concentrations of folate, but not vitamins B6 and B12, are correlated with atrophy of the cerebral cortex on autopsy, a surrogate marker of neurodegenerative disease Citation[11]. Homocysteine levels over 14 µmol/l doubled the risk of AD in the Framingham study Citation[7], but there was no relationship between the blood levels of folate, vitamin B6 and B12 and the risk of AD. A study from New York (NY, USA) found that the association between high homocysteine levels and AD was confounded by age Citation[12] and there was no association between a level of homocysteine over 14 µmol/l, the usual limit of normal, and the risk of AD. However, several more prospective studies have found associations between homocysteine and AD Citation[13], and the New York study is one of the few reporting no association. Since homocysteine is clearly influenced by dietary intake of vitamins B12 and B6, and folate, it is presumed that homocysteine is a potential mechanism for a relationship of these vitamins with cognitive disorders, including AD.
Several studies have found that homocysteine-related vitamins are associated with AD risk. One study, comprised of 370 persons without dementia at baseline aged 75 years and older, found that, during 3 years of follow-up, subjects with lower vitamin B12 or folate levels (B12 ≤ 150 pmol/l and folate ≤ 10 nmol/l) had twice the risk of developing AD compared with individuals with higher levels Citation[14]. Conversely, another study of 410 subjects aged between 75 and 85 years followed for 5 years with low B12 levels (<150 pg/ml) showed no increased risk Citation[15]. One study in Chicago (IL, USA) found no association between dietary folate, B6, B12 and AD Citation[16], and the same group surprisingly found that higher folate intake was related to a higher risk of cognitive decline Citation[17]. A study in New York found that folate, but not vitamins B6 and B12, was related to a lower risk of AD, although there was no relationship between homocysteine and AD in the same study. This association was stronger when vitamins B12 and B6 were taken into account Citation[18]. One of the potential interpretations of this study is that folate could have an effect on AD not related to homocysteine, although this is not clear.
Since 1998, cereal grain products in the USA have been fortified with folic acid. This supplementation has been accompanied by decreases in homocysteine levels in the general population Citation[19]. Folic acid fortification in women of childbearing age has resulted in a decrease in the incidence of neural tube defects Citation[20], an important public health success. However, the effects of folic acid fortification for the population at large remain to be determined. There is concern that folic acid fortification may improve anemia in elderly persons with B12 deficiency but could exacerbate neuropsychiatric complications, either owing to masking of B12 deficiency or other mechanisms Citation[21]. A recent cross-sectional analysis of the National Health and Nutrition Examination Survey data showed that, in elderly people with low serum B12, high folate levels were related to cognitive impairment and anemia Citation[21]. This observation could be due to masking of B12 deficiency but could also be due to an unknown effect of an interaction between low B12 and high folate levels.
There are few trials studying the cognitive effects of homocysteine lowering with vitamins. A trial of the supplementation of folate, B6 and B12 in the secondary prevention of stroke found no benefit Citation[22]. However, a recent meta-analysis of trials of folic acid supplementation found that there was an apparent benefit for stroke Citation[23], particularly in situations in which there is no fortification of foods with folic acid, where supplementation lasted more than 36 months and when there was no history of stroke. Thus, it is possible that folic acid supplementation is effective in primary prevention of stroke and could prevent cognitive disorders, including AD, through cerebrovascular mechanisms.
A 2-year, double-blind, placebo-controlled, randomized clinical trial of homocysteine-lowering treatment with folate, B6 and B12 supplements in 276 participants, 65 years of age or older, with plasma homocysteine concentrations of at least 13 µmol/l found a lower homocysteine level in the treatment group, but no difference in cognition at 2 years Citation[24]. A secondary analysis with a composite measure of cognition revealed a higher risk of cognitive decline of borderline statistical significance, consistent with the findings from Morris in Chicago Citation[17].
Given conflicting evidence relating to dietary and supplemental folate and vitamin B6 and B12, it seems reasonable at this time to state that supplementation of these vitamins should be reserved for the treatment of documented deficiency states, but not expressly for the prevention or treatment of cognitive disorders, including AD. Clinicians often make recommendations of vitamin supplementation based on the premise that, while they may not be helpful, they are not harmful, assuming a favorable risk:benefit ratio. However, at least one observational study and one clinical trial found an association between homocysteine-related vitamin intake and cognitive decline, and this finding must be clarified. In addition, purchasing vitamin supplements with uncertain benefits (beyond food fortification) and possible adverse effects could be an additional financial burden for elderly individuals who may live on a modest fixed income.
In conclusion, existing data do not support supplementation with folate, vitamins B6 and B12 for the prevention of AD or any other cognitive disorder.
Financial disclosure
The author has no relevant financial interests related to this manuscript, including employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
References
- Cummings JL. Alzheimer’s disease. N. Engl. J. Med.351, 56–67 (2004).
- Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am. J. Public Health88, 1337–1342 (1998).
- Selkoe DJ. Alzheimer’s disease: genotypes, phenotypes, and treatments. Science275, 630–631 (1997).
- Luchsinger J, Mayeux R. Cardiovascular risk factors and Alzheimer’s disease. Curr. Atheroscler. Rep.6, 261–266 (2004).
- Selkoe DJ. The origins of Alzheimer disease: a is for amyloid. JAMA283, 1615–1617 (2000).
- Luchsinger JA, Mayeux R. Dietary factors and Alzheimer’s disease. Lancet Neurol.3, 579–587 (2004).
- Seshadri S, Beiser A, Selhub J et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N. Engl. J. Med.346, 476–483 (2002).
- Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA270, 2693–2698 (1993).
- Rasmussen K, Moller J, Lyngbak M, Pedersen AM, Dybkjaer L. Age- and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. Clin. Chem.42, 630–636 (1996).
- Seshadri S, Wolf PA. Homocysteine and the brain: vascular risk factor or neurotoxin? Lancet Neurol.2, 11 (2003).
- Snowdon DA, Tully CL, Smith CD, Riley KP, Markesbery WR. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun study. Am. J. Clin. Nutr.71, 993–998 (2000).
- Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R. Plasma homocysteine levels and risk of Alzheimer disease. Neurology62, 1972–1976 (2004).
- Haan MN, Miller JW, Aiello AE et al. Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the Sacramento Area Latino Study on Aging. Am. J. Clin. Nutr.85, 511–517 (2007).
- Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer’s disease. Neurology56, 1188–1194 (2001).
- Crystal HA, Ortof E, Frishman WH, Gruber A, Hershman D, Aronson M. Serum vitamin B12 levels and incidence of dementia in a healthy elderly population: a report from the Bronx Longitudinal Aging Study. J. Am. Geriatr. Soc.42, 933–936 (1994).
- Morris MC, Evans DA, Schneider JA, Tangney CC, Bienias JL, Aggarwal NT. Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer’s disease. J. Alzheimers Dis.9, 435–443 (2006).
- Morris MC, Evans DA, Bienias JL et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch. Neurol.62, 641–645 (2005).
- Luchsinger JA, Tang MX, Miller J, Green R, Mayeux R. Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch. Neurol.64, 86–92 (2007).
- Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N. Engl. J. Med.340, 1449–1454 (1999).
- Lumley J, Watson L, Watson M, Bower C. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Syst. Rev.3, CD001056 (2001).
- Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am. J. Clin. Nutr.85, 193–200 (2007).
- Toole JF, Malinow MR, Chambless LE et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA291, 565–575 (2004).
- Wang X, Qin X, Demirtas H et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet369, 1876–1882 (2007).
- McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N. Engl. J. Med.354, 2764–2772 (2006).