Data obtained in the recent prospective epidemiological studies of Wolf et al. and in our studies of a mouse model of Alzheimer's disease (AD) provide a strong case for folic acid supplementation as a preventative approach for AD. The study of the Framingham cohort suggests that elevated plasma homocysteine levels is an independent risk factor for AD, but did not allow a conclusion as to if and how homocysteine promotes neuronal dysfunction and death. We found that maintaining AβPP-mutant mice with Aβ deposits in their brains on a folic acid deficient diet results in elevated plasma homocysteine levels and degeneration of neurons in their hippocampus. The endangering effect of folic acid deficiency was not the result of increased production of Aβ peptide; instead, homocysteine rendered hippocampal neurons vulnerable to Aβ peptide-induced cell death. The mechanism whereby homocysteine endangers neurons involves an impairment of DNA repair, and the resulting accumulated DNA damage triggers apoptosis. Thus, we have established a cause-effect...  Read more

Data obtained in the recent prospective epidemiological studies of Wolf et al. and in our studies of a mouse model of Alzheimer's disease (AD) provide a strong case for folic acid supplementation as a preventative approach for AD. The study of the Framingham cohort suggests that elevated plasma homocysteine levels is an independent risk factor for AD, but did not allow a conclusion as to if and how homocysteine promotes neuronal dysfunction and death. We found that maintaining AβPP-mutant mice with Aβ deposits in their brains on a folic acid deficient diet results in elevated plasma homocysteine levels and degeneration of neurons in their hippocampus. The endangering effect of folic acid deficiency was not the result of increased production of Aβ peptide; instead, homocysteine rendered hippocampal neurons vulnerable to Aβ peptide-induced cell death. The mechanism whereby homocysteine endangers neurons involves an impairment of DNA repair, and the resulting accumulated DNA damage triggers apoptosis. Thus, we have established a cause-effect relationship between elevated homocysteine levels and neuronal degeneration.

Importantly, we have also shown that dietary supplementation with folic acid can protect neurons against amyloid toxicity, suggesting that folic acid may not only prevent AD, but may also slow the neurodegenerative process in symptomatic AD patients who already have extensive amyloid deposition in their brain. It should also be noted that recent studies suggest that folic acid deficiency and elevated homocysteine levels can render dopaminergic neurons vulnerable to dysfunction and death in experimental models of Parkinson disease (Duan et al., 2002). In light of the growing epidemics of Alzheimer's and Parkinson's in this country, I would strongly encourage the FDA to move quickly to establish recommendations to the public that ensure all Americans receive a neuroprotective amount of folic acid, and that clinical trials move forward as rapidly as possible to establish efficacy of folic acid supplementation in patients with neurodegenerative disorders."—Mark Mattson, NIA Gerontology Research Center, Baltimore, Maryland.

"This interesting paper by Kruman et al. demonstrates that folic acid deficiency and increased homocysteine levels are toxic to neuronal cells. Using cultured neurons and transgenic mice, these authors demonstrate that folic acid deprivation and increased levels of homocysteine render neuronal cells vulnerable to excitotoxic insults (Kruman et al. 2000) and Aβ toxicity by increasing DNA damage. Furthermore, Kruman and co-workers established that folic acid deficiency induced DNA damage by impairing DNA repair mechanisms in neurons exposed to Aβ. One important implication of this study is that, in the Alzheimer brain, folic acid deficiency and increased homocysteine levels may accelerate the accumulation of DNA damage that is promoted by Aβ.

The importance of these results is underscored by a recent prospective study by Seshadri et al. that established a strong correlation between increased homocysteine plasma levels and the development of Alzheimer's. Homocysteine plasma level has been shown to be a major vascular risk factor and it is generally recognized that cardiovascular risk factors and stroke increase the risk of vascular dementia and Alzheimer's disease. Future studies should be directed to determine whether reduction of homocysteine plasma levels could effectively reduce the risk of Alzheimer's disease. Taken together, these studies indicate that dietary supplementation of folic acid and vitamins B6 and B12 may decrease the risk of Alzheimer's disease.

View all comments by Jorge Busciglio

In this prospective study, Seshadri et al. measured plasma homocysteine levels in normal elderly individuals and then followed the same individuals for eight years and reassessed their clinical status as well as homocysteine levels. They found that plasma homocysteine was a risk factor for the development of dementia in general as well as dementia felt to be secondary to Alzheimer's disease. Homocysteine levels are a known risk vactor for vascular disease. Whether homocysteine itself is directly related to the risk for the dementia or is a surrogate marker for something else is not clear.

The study is important as it suggests that further understanding of why homocysteine is in some way related to dementia is warranted. Homocysteine can be lowered by folic acid leading some to speculate that prospective trials of folic acid are indicated. One potential problem with the study is that for subjects to be called demented, they had to have a clinical dementia rating score of 1 (mildly demented). dementia due to Alzheimer's disease is often present clinically from four to eight...  Read more

In this prospective study, Seshadri et al. measured plasma homocysteine levels in normal elderly individuals and then followed the same individuals for eight years and reassessed their clinical status as well as homocysteine levels. They found that plasma homocysteine was a risk factor for the development of dementia in general as well as dementia felt to be secondary to Alzheimer's disease. Homocysteine levels are a known risk vactor for vascular disease. Whether homocysteine itself is directly related to the risk for the dementia or is a surrogate marker for something else is not clear.

The study is important as it suggests that further understanding of why homocysteine is in some way related to dementia is warranted. Homocysteine can be lowered by folic acid leading some to speculate that prospective trials of folic acid are indicated. One potential problem with the study is that for subjects to be called demented, they had to have a clinical dementia rating score of 1 (mildly demented). dementia due to Alzheimer's disease is often present clinically from four to eight years prior to someone reaching this stage. Thus, some of the individuals who were felt to be "normal" at baseline in this study were probably in the earliest clinical stages of dementia. Thus, homocysteine elevation may not necessarily have preceded clinical disease. Nonetheless, this is an important study that should lead to further work.

View all comments by David Holtzman

Our findings in B6-deficient diet are based on the controversial situation of homocysteine risk factor for Alzheimer disease. The New England Journal of Medicine reported that administration of vitamin B6, folic acid and vitamin B12 to older persons did not prevent their cognitive decline, and the author expressed doubt of the homocysteine risk factor. But our B6-deficient condition suggested that homocysteic acid is indeed a real risk factor. B6-deficient food induced a high level of homocysteine, homocysteic sulfonic acid, and homocysteic acid. Then B6-deficient condition is a good means for inducing the homocysteine risk factor in 3xTg-AD mice. Our anti-HA antibody or vaccine treatment did give a strong answer that homocysteic acid is a real risk factor of homocysteine risk and consequently is a real pathogenic factor.

Recently many papers reported that homocysteine induced Aβ40/42, and these phenomena may be related to the homocysteine risk factor for Alzheimer disease. But recent unsatisfactory results of clinical amyloid treatments raised doubt about the amyloid...  Read more

Our findings in B6-deficient diet are based on the controversial situation of homocysteine risk factor for Alzheimer disease. The New England Journal of Medicine reported that administration of vitamin B6, folic acid and vitamin B12 to older persons did not prevent their cognitive decline, and the author expressed doubt of the homocysteine risk factor. But our B6-deficient condition suggested that homocysteic acid is indeed a real risk factor. B6-deficient food induced a high level of homocysteine, homocysteic sulfonic acid, and homocysteic acid. Then B6-deficient condition is a good means for inducing the homocysteine risk factor in 3xTg-AD mice. Our anti-HA antibody or vaccine treatment did give a strong answer that homocysteic acid is a real risk factor of homocysteine risk and consequently is a real pathogenic factor.

Recently many papers reported that homocysteine induced Aβ40/42, and these phenomena may be related to the homocysteine risk factor for Alzheimer disease. But recent unsatisfactory results of clinical amyloid treatments raised doubt about the amyloid pathogen of Alzheimer disease.

Our findings in B6-deficient conditions give a strong reply that amyloid beta is not related to the homocysteine risk factor and that homocysteic acid is a real homocysteine risk factor.

The manuscript with our findings on anti-HA antibody treatment in 3xTg-AD mice is available at Nature Precedings

View all comments by Tohru Hasegawa