Even as vitamin E appears to be losing some of its memory-saving appeal, the B vitamin folate (i.e. folic acid) is becoming the nutrient du jour. Besides helping to prevent birth defects, it probably reduces the risk of heart disease, stroke, and some cancers. And now, two articles suggest that folate supplementation could help prevent or even treat Alzheimer's disease.
The value of folate-found especially in leafy greens, fruits, vegetables, and yeast-stems from the fact that it helps keep the amino acid homocysteine at low levels. But how might homocysteine contribute to Alzheimer's? In today's Journal of Neuroscience, Mark Mattson, Inna Kruman, and colleagues at the National Institute on Aging and Johns Hopkins University, both in Baltimore, Maryland, directly link folate and homocysteine to amyloid toxicity. Hypothesizing that high homocysteine levels promote the accumulation of DNA damage, they demonstrate that hippocampal neurons cultured without folate, or with added homocysteine, undergo elevated levels of apoptosis. This culture environment further rendered neurons vulnerable to added Aβ1-42. Rather than working in concert with Aβ to damage neurons, or damaging DNA directly, high homocysteine levels appear to interfere with the cell's efforts to repair Aβ-induced oxidative modification of DNA bases.
These in vitro results stood when tested in AβPP-transgenic mice, which overproduce and deposit Aβ. Relative to mutant mice fed a normal diet, those deprived of folate showed increased cellular DNA damage and hippocampal neurodegeneration. This occurred despite any difference in brain Aβ levels between the two groups.
What does the epidemiology say? Conflicting studies on the proposed link between Alzheimer's and high homocysteine levels have left the question unsettled. Enter Philip Wolf, Sudha Seshadri, and colleagues at Boston University and at the U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University in Boston. In the February 14 New England Journal of Medicine, these authors report that a five-micromolar increment in plasma homocysteine level increased the risk of getting Alzheimer's by 40 percent. The data come from a large prospective study, in which 1,092 dementia-free subjects from the Framingham cohort had their homocysteine levels tested eight years prior to the baseline examination for dementia, and were followed for an average of eight years. The effect was independent of age, sex, ApoE genotype, and other AD risk factors.
Where does all this leave humans, besides awaiting more studies? If you simply follow the familiar nutrition pyramid-high in green vegetables, fruits, and whole grains-you eat the foods highest in folate, but may still not be getting enough to reduce homocysteine to innocuous levels. For that reason, the FDA now mandates that some staple foods contain added folate. The question this raises for future studies is whether even higher quantities are required to protect against Alzheimer's and other diseases, and whether such quantities are safe.—Hakon Heimer
No Available References
- Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, Haughey N, Lee J, Evans M, Mattson MP. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J Neurosci. 2002 Mar 1;22(5):1752-62. PubMed.
- Mattson MP, Kruman II, Duan W. Folic acid and homocysteine in age-related disease. Ageing Res Rev. 2002 Feb;1(1):95-111. PubMed.
- Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002 Feb 14;346(7):476-83. PubMed.