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...
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...