High folic acid intake is associated with reduced incidence of both heart disease (
) and colon cancer (
). For heart disease at least, the mechanism is thought to be that of reducing
homocysteine levels. The bottom line is that low folate and high homocysteine are
bad, while high folate and low homocysteine are good. The question was asked of
whether there was a similar association with dementia.
Some quick searching revealed that there is, indeed, a literature on this. It seems
to confirm a similar relationship between high folate intake (or at least levels),
low serum homocysteine and low risk of dementia. Three epidemiological studies are
Thirty patients aged 65 years or more (mean age 79 years) and presenting
consecutively with features compatible with primary degenerative dementia of
Alzheimer's type were matched with controls from the local general practice
population without dementia. There were several sensible exclusions.
Homocysteine levels were much lower in controls than in patients with dementia
(Figure 1), which was significant at the 1 in 10,000 level. Folate levels were
somewhat lower in controls, but the two major discriminating factors between patients
and controls were homocysteine and folate.
Figure 1: Homocysteine levels in patients with dementia and age-matched
In Canada, a population study of people over 65 had 1171 individuals in whom
serum folate was measured as part of a clinical examination in a study of ageing.
The clinical features of the patients were then examined according to the
quartile of folate results. Those in the highest quartile had lower rates of
dementia and depression, and were less likely to be institutionalised (Figure 2).
When dementias were examined closely, there were significant differences between
the quartile with the highest level of folate and the lowest for any type of
dementia, for probable plus possible Alzheimer's disease, and for other types of
dementia than vascular or unclassified types. Older age groups were selectively
sampled (mean age 82 years), explaining the high incidence of dementia.
Figure 2: Comparison between outcomes with high and low serum folate in
Perhaps the most detailed of these three studies was that conducted in Oxford on
164 patients over 55 with a clinical diagnosis of Alzheimer's disease and 108
matched controls. This looked at a range of markers in blood, including some
genetic markers. Importantly, 76 of the patients subsequently died, and their
Alzheimer's disease was confirmed by histology on post mortem examination.
Serum homocysteine was significantly lower, and folate higher, in controls than
in patients. The frequency of the Apo E lipoprotein allele eta-4 occurred at
about 40% in patients with Alzheimer's disease than in controls. Moreover, in 43
patients with clinically diagnosed Alzheimer's disease with CAT scans over four
years there was significantly radiological evidence of disease progression in
those with the middle and highest tertiles of homocysteine compared to those in
The association between high serum homocysteine and low serum folate and
dementia appears to be reproducible. Is it cause or effect? One suggestion is
that people with dementia have poor diets - they may lose weight and have low
serum albumin levels - because of their disease. So that could explain the low
folate intake and high homocysteine levels. There is no easy answer to this, but
the Oxford study demonstrated that homocysteine and vitamin levels were stable
over several years while dementia got worse.
Clearly some prospective trials will be needed to sort out the benefits of
treatment, and more about the underlying processes. The bottom line is that
taking a daily multivitamin for whatever reason is likely to prevent
cardiovascular disease, cancer and possibly dementia also.
- A McCaddon et al. Total serum homocysteine in senile dementia of Alzheimer
type. International Journal of Geriatric Psychiatry 1998 13: 235-9.
- EM Ebly et al. Folate status, vascular disease and cognition in elderly
Canadians. Age and Ageing 1998 27: 485-491.
- R Clarke et al. Folate, vitamin B12, and serum total homocysteine levels in
confirmed Alzheimer disease. Archives of Neurology 1998 55: 1449-55.
story in this issue