Psychiatric Times.
No. 11
The Role of B Vitamins, Homocysteine in AD and Vascular Dementia
By Aron Troen, Ph.D., and Irwin H. Rosenberg, M.D. |
November 1, 2002
Dr. Troen is postdoctoral research associate at Tufts USDA HNRC Vitamin Metabolism & Nutrition and Neurocognitive Laboratories.
Dr. Rosenberg is a senior scientist at the Jean Mayer USDA Human Nutrition Research Center on Aging, dean of nutrition sciences and professor of nutrition at Tufts University.
Possible Causative Risk
These epidemiological observations are consistent with the view that vascular dementia and AD share some common pathological mechanisms. The role of hyperhomocysteinemia is particularly interesting in this context, because plasma homocysteine can be safely lowered by relatively inexpensive nutritional intervention and vitamin supplements, which could conceivably reduce the associated risk (Homocysteine Lowering Trialists' Collaboration, 1998; Selhub et al., 2000b). However, association does not prove causality. Alternative explanations include the possibilities that these associations are secondary to disease-related metabolic disturbances, or the trivial explanation that they reflect a reduction in dietary intake with increasing severity of cognitive decline and dementia (Riviere et al., 1999). Even the early rise in homocysteine levels, which seems to increase the likelihood of subsequent dementia, could be secondary to other disease-related processes (Brattstrom and Wilcken, 2000). Nevertheless, elevated plasma homocysteine apparently reflects an early involvement of impaired one-carbon metabolism in AD (Figure).
In order to validate homocysteine as a causative risk factor for AD, two conditions must be satisfied: the epidemiological association must be shown to be causal, and the pathological mechanism underlying this association must be elucidated. Satisfying both conditions requires the application of complementary epidemiological and biochemical approaches to the problem.
Demonstrating causality can only be done in an experimental study by reducing the exposure of a treatment population to homocysteine while holding all other factors constant. Currently, several trials are planned or underway to test the benefit of B vitamin supplementation in lowering homocysteine and, in turn, preventing dementia or slowing its progression. Successful outcomes will support a causal role for homocysteine in AD and point to a considerable public health benefit of homocysteine-lowering. If, however, the trials successfully lower homocysteine without preventing cognitive decline, the relation of homocysteine to AD will remain uncertain.
A variety of theoretical mechanisms have been invoked to account for the association of homocysteine with AD and cognitive decline (see Selhub et al. [2000a] for a review). Homocysteine might contribute to thromboembolism of large vessels through damage to the endothelial cells that line the vessels, or by harming the brain capillaries (composed of a single layer of endothelial cells) that make up the blood-brain barrier. Homocysteine might also poison groups of neurons that have N-methyl-D-aspartate receptors (e.g., hippocampal pyramidal cells that are particularly vulnerable to AD pathology) (Lipton et al., 1997). There is considerable experimental evidence (largely in vitro) supporting such cytotoxic effects of homocysteine, but their relevance in vivo is uncertain, particularly in the brain where they have never been tested.
Alternatively, elevated plasma homocysteine might reflect the accumulation in the cells of its precursor, S-adenosylhomocysteine (SAH), a potent inhibitor of methylation reactions. Several important neurological processes require methylation, which, if disrupted significantly, could have a profound impact on neurological function. Furthermore, impaired one-carbon metabolism has also been linked to DNA damage (Duan et al. 2002; Kruman et al., 2002; Kruman et al., 2000) and altered metabolism of biogenic amines (e.g., dopamine(Drug information on dopamine), norepinephrine(Drug information on norepinephrine), serotonin) (Gospe et al., 1995; Hamon et al., 1986). Folate and vitamin B12 are necessary cofactors for normal brain metabolism, and severe deficiencies of either one will directly impair neurological function. This necessity, together with their intimate metabolic relationship to homocysteine, makes it difficult to dissociate the putative toxicity of homocysteine from the potentially harmful effects of inadequate folate or vitamin B12 status.
These and other questions will need to be addressed in order to fully understand the observed epidemiological relation of impaired one-carbon metabolism (elevated homocysteine and deficient B vitamins) to AD, and to justify widespread screening for tHcy and population-based vitamin intervention.
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