Hyperhomocysteinemia and cognitive function: more than just a casual link?

Over the past 2 decades, numerous epidemiologic studies have confirmed that elevated plasma total homocysteine (tHcy) is associated with an increased risk of vascular diseases, including cardiovascular, peripheral vascular, and cerebral vascular disease (1, 2). Because elevated plasma tHcy is effectively treated with B vitamin supplements (folic acid, vitamin B-12, and vitamin B-6), therapy that is inexpensive and well tolerated, an explosion of clinical and basic research on the vascular effects of hyperhomocysteinemia has occurred over the past decade. Vascular disease has deleterious effects on various organs of the body, and the brain is particularly susceptible. Elevated tHcy is now a recognized risk factor for vascular dementia. More surprising have been a series of observations from cross-sectional and prospective epidemiologic studies that elevated tHcy is associated with an increased risk of Alzheimer disease (AD) and with cognitive problems in the elderly that fall short of dementia. In this issue of the Journal, Ravaglia et al (3) present the latest data on this issue, which led them to conclude that elevated plasma tHcy and low serum folate concentrations are independent predictors of AD development. The prospective and longitudinal nature of this study provides an important measure of confidence to their conclusions. The authors point out that several case-control and cross-sectional studies have reported an association between AD and elevated plasma tHcy. However, only 2 prospective longitudinal studies, which have conflicting results, have appeared in the literature. The findings of the current study by Ravaglia et al confirm previous findings from the Framingham Study (4), which indicate that hyperhomocysteinemia is associated with a 2-fold increase in the relative risk of developing AD. The negative findings from the Washington Heights–Inwood Columbia Ageing Project (WHICAP) (5) were dismissed on the basis of insufficient statistical power and other methodologic issues. There are other important findings of the study by Ravaglia et al. The increased risk of developing AD in hyperhomocysteinemic persons remained unchanged even after subjects with brain imaging evidence of vascular disease were excluded. Although elevated tHcy may promote vascular disease that contributes to AD pathology, it may also have other direct neurotoxic effects. Another interesting aspect of this study, which was conducted in Italy (where food fortification is not mandated), was the observation that low folate status is independently associated with an increased risk of developing AD—a finding not evident in the Framingham Study or WHICAP. Another article in this issue, by Tucker et al (6), presents data on the relation between tHcy, B vitamins, and cognitive decline that falls short of dementia. Study subjects from the VA Normative Aging Study were assessed over a 3-y period before the fortification of food sources with folate. On the basis of both plasma concentrations and dietary intake assessments, this longitudinal study showed that tHcy, folate, vitamin B-12, and vitamin B-6 are independently associated with various measures of cognitive decline. Although elevated plasma tHcy was shown to be associated with memory recall, low plasma folate was shown to be associated with constructural praxis after adjustment for tHcy and other B vitamins. These independent associations highlight a central argument in this field of research: whether elevated plasma tHcy is merely a marker for deficiencies in folate and other B vitamins or whether it is more directly involved in cognitive function and dementia. Recent data from studies in Parkinson disease (PD) argue for a more direct neurotoxic role for Hcy in central nervous system function. In the setting of L-dopa therapy for PD, hyperhomocysteinemia results from an excessive methylation burden rather than from a vitamin deficiency, and PD patients with elevated plasma tHcy and normal B vitamin status are more likely to be cognitively impaired and depressed (7). Epidemiologic studies, even when elegantly designed and rigorously conducted, cannot address the issue of causality. The available data are consistent with the hypothesis that elevated tHcy is toxic to the nervous system; however, the possibility that elevated plasma tHcy is simply a marker of an underlying neurodegenerative process cannot be excluded. In the latter case, therapy aimed at correcting hyperhomocysteinemia will not be effective at correcting neurodegeneration. Studies to address this important issue will have to focus in 2 directions. First, molecular and animal model studies are needed to identify as precisely as possible the neuropathogenic mechanisms associated with tHcy elevations. The metabolic relations between homocysteine, folate, and B vitamins are intimate and complex. The consequences