Elevated plasma homocysteine levels: Risk factor or risk marker for the development of dementia and Alzheimer's disease?

Elevated plasma homocysteine (tHcy) concentrations have been associated with an increased risk of developing dementia and Alzheimer's disease (AD). It is not clear, however, if an elevation in tHcy concentration is a 'risk factor' with a direct pathophysiological role in the development of the disease or merely a 'risk marker' reflecting an underlying process such as oxidative stress responsible for both the high tHcy concentrations and the development of AD. Epidemiological studies have confirmed that elevations in plasma tHcy temporally precede the development of dementia and that there is a continuous, inverse linear relation between plasma tHcy concentrations and cognitive performance in older persons. Several potential biological pathways that could mediate the observed association are briefly reviewed. In light of these data and the growing parallel interest in plasma tHcy as an emerging vascular risk factor there was considerable hope that vitamin therapy with folate, B₁₂ and B₆, shown to lower plasma tHcy levels, could significantly reduce the risk of stroke and dementia permitting healthy brain aging. The results from recent trials addressing the secondary prevention of stroke and myocardial infarction trials have been disappointing. However, the role of vitamins and other homocysteine lowering treatments in the primary prevention of stroke and dementia, as well as their role in preserving cognition among persons with mild cognitive impairment and early dementia deserves to be fully pursued.