Sudeep S. Gill, MD, FRCP(C), Research Fellow, Division of Geriatric Medicine, University of Toronto and Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care, Toronto, ON.
Shabbir M.H. Alibhai, MD, MSc, FRCP(C), Staff Physician, Department of Medicine, University Health Network, Toronto, ON.

Folate deficiency is relatively common in older adults. There is now growing interest in the roles played by folate and B vitamins in the metabolism of homocysteine. Recent studies have suggested a link between elevated levels of homocysteine and the risk of Alzheimer disease. In this article, we will focus on the physiology and pathophysiology related to folate and homocysteine metabolism. We have also included a discussion of the laboratory evaluation of these compounds. Finally, we review the evidence supporting the relationships between folate deficiency, hyperhomocysteinemia and the development of dementia.
Key words: folic acid, vitamin B12, deficiency diseases, homocysteine, dementia.

Cross-sectional studies have indicated that elevated plasma homocysteine levels are associated with poor cognition and dementia. As elevated plasma homocysteine levels might result from poor nutrition and vitamin deficiencies, both easily modifiable factors, a group of researchers decided to investigate whether elevated homocysteine levels precede the onset of dementia.

The group studied 1,092 subjects without dementia (667 women and 425 men; mean age 76 years) from the Framingham study cohort. The researchers examined the relationship between plasma total homocysteine measured at baseline and that measured eight years earlier, to the risk of newly diagnosed dementia at follow-up. Adjustments were made for a number of factors including age, sex, apolipoprotein E genotype, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B12 and B6. A committee, comprised of at least two neurologists and a neuropsychologist, evaluated the patients and made the final diagnosis.

Over a median follow-up of eight years, 111 subjects developed dementia: 83 AD, 11 vascular dementia, 11 non-Alzheimer degenerative dementia and other types of dementia in 6 subjects. The results suggested that there is a strong, graded association between plasma total homocysteine levels and the risk of dementia and Alzheimer disease. An increment in the plasma homocysteine level of 5 mol per litre increased the risk of AD by 40% and a plasma homocysteine level in the highest age-specific quartile doubled the risk of dementia or AD.

Unfortunately, the results of the study do not determine whether or not this is a modifiable factor. Additionally, there is a lack of racial diversity in the overwhelmingly white Framingham cohort. Other cohort studies and controlled trials will be necessary to determine if there is a causal relationship between homocysteine and dementia.

In the meantime, don't forget to eat a healthy diet including green, leafy vegetables and enriched cereal grain products, to ensure adequate intake of folic acid and vitamins B6 and B12.

Source

1. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. NEJM 2002; 346:476-83.