| The most common form of senility is Alzheimer’s
disease, which accounts for more than 70% of all dementia cases.
People with cardiovascular risk factors and a history of strokes
have an increased risk of both vascular (arteriosclerotic) dementia
and Alzheimer’s disease.
Elevated plasma homocysteine (hyperhomocysteinemia) is now recognized
as a strong, independent risk factor for stroke and dementia.
Hyperhomocysteinemia
is caused by deficiencies in vitamins B6, B12 and folic acid.1 The adverse vascular and neurotoxic effects of homocysteine are
associated with excess free radical generation (oxidative stress).2
Elevated plasma homocysteine, however, is a reversible risk factor. Consumption
of foods containing B vitamins and supplementation with folic acid and vitamins
B6 and B12 are the primary preventive and therapeutic treatments. The intake
of antioxidants through diet and supplements protects against oxidant stress
and helps maintain the normal function of the vascular system and brain.1,3
Elevated Homocysteine—Potentially Lethal
Homocysteine is a toxic, sulfur-containing
amino acid formed from the amino acid methionine. Under normal metabolic conditions,
homocysteine is removed from the circulatory system by recycling back to methionine,
in a chemical reaction (re-methylation) that requires folate and vitamin B12.
Another means of homocysteine disposal is its conversion (transsulforation)
to the amino acid cysteine, in a reaction that requires vitamin B6.
In hyperhomocysteinemia, homocysteine levels can range from 14 micromoles/liter
all the way up to 100 micromoles/liter in severe cases.1 Genetic factors such
as mutations in genes that regulate folate and vitamin B6 metabolism, as well
as severe renal disease, increase homocysteine levels.
Elevated homocysteine damages endothelial cells that line blood vessels and
induces thrombosis that can lead to heart attacks and stroke. Homocysteine
produces breaks in DNA and induces apoptosis (a programmed cell suicide) that
is a major cause of neuronal death in dementia.4
An increase in homocysteine affects multiple organs during aging. Humans with
inherited defects in enzymes involved in homocysteine detoxification show features
of accelerated aging and a marked propensity for age-related diseases.
Homocysteine, B Vitamins Closely Linked
Recent studies in the UK and Norway
of people 65 years and older and of young people ages 4 to 18 found that
plasma homocysteine levels increase progressively with age and are directly
related to plasma levels of folate and vitamins B12 and B6. The lower the
B vitamin levels, the higher was the homocysteine concentrations.5
Along the same lines, a high intake of vitamins B6 and B12 along with folic
acid substantially lowers homocysteine, as reported recently by Dr. den Heijer
at the XIX Congress of the International Society on Thrombosis and Haemostasis,
held in July 2003 in the UK. In a randomized study, 353 patients received high
daily doses of folic acid (5 mg), vitamin B6 (50 mg), and vitamin B12 (0.4
mcg), while 353 patients received a placebo. Three months later, the vitamin-supplemented
group had a 30-40% decrease in homocysteine levels, compared to patients on
placebo. The results emphasize the importance of B vitamin supplementation
to offset age-related declines in vitamin levels and counteract age-related
increases in homocysteine.
High Homocysteine Implicated in Dementia
The association between high levels
of homocysteine and dementia—including
Alzheimer’s disease—has been observed in epidemiological studies
and confirmed in case-control studies in which patients with vascular dementia
and Alzheimer’s disease had higher levels of homocysteine than did healthy
people.6
A direct link between increases in plasma homocysteine and loss of cognition
was shown by Seshardi et al at the Boston University School of Medicine and
reported in the New England Journal of Medicine (Feb. 14, 2002).
The study, part of the ongoing Framingham Heart Study, provides compelling
evidence that in adults with intact cognition, an elevation in plasma homocysteine
over time is associated with an increased incidence of dementia, including
Alzheimer’s
disease. The results also underscore the importance of B vitamin supplementation
for preventing homocysteine-associated dementia.1
The study enrolled 1,092 elderly subjects without dementia (667 women and 425
men), with a mean age of 76 years. Over a median follow-up period of eight
years, dementia (including vascular dementia and other types of non-Alzheimer’s
dementia) developed in 111 subjects (10.2%; 74 women and 37 men), and 83 of
these subjects (62 women and 21 men) were diagnosed with Alzheimer’s
disease. Hyperhomocysteinemia (plasma homocysteine higher than the baseline
of 14 micromoles per liter) doubled the risk of dementia or Alzheimer’s
disease in the subjects with the highest levels of homocysteine. An estimated
16% of the observed incidences of Alzheimer’s disease were attributable
to hyperhomocysteinemia.
Increases in homocysteine levels occurred well before the onset of clinical
signs of dementia, and there was a strong association between homocysteine
levels and risk; that is, an increment increase of 5 micromoles per liter of
homocysteine raised the risk of Alzheimer’s disease by 40%.
The study’s authors also found that the homocysteine-related doubling
of risk of dementia was of the same magnitude as the increased risk of death
from cardiovascular disease and stroke (a twofold increase) seen in earlier
studies.
The study concluded that “An increased plasma homocysteine level is a
strong, independent risk factor for the development of dementia and Alzheimer’s
disease” and that “vitamin therapy with folic acid, alone or
in combination with vitamins B6 and B12 and dietary supplementation with
enriched-grain products and breakfast cereal containing folate can reduce
plasma homocysteine levels.”1
A recent study in Australia examined the brains of 36 healthy seniors and found
that those with high homocysteine levels were twice as likely to show a loss
of brain cells compared to those with normal homocysteine levels.7
Another study, from Queens University in Belfast, Northern Ireland, published
in Stroke in October 2002, found that moderately high levels of homocysteine
were associated with significant increases in the risk of Alzheimer’s
disease, vascular dementia, and stroke, compared with people with lower levels
of homocysteine. Increases in homocysteine were not related to any genetic
defect that affects folate metabolism and raises homocysteine. The study concluded
that since B vitamins and folate-fortified foods can reduce homocysteine levels,
B-vitamin supplementation may be appropriate for most adults, and that the
study results warrant a placebo-controlled study of folate and vitamins B6
and B12 in people who are at risk for stroke and dementia.8 An accompanying
editorial advised that because people differ in their dietary habits, supplementation
with 2000-5000 mcg of folic acid daily and a similarly safe dose of vitamin
B12 may be appropriate.
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How Hyperhomocysteinemia Leads to Dementia
Numerous studies offer clues as
to the various ways in which high levels of homocysteine induce the vascular
and neuronal damage implicated in the development of dementia.
Vascular effects. The Nun study of aging and Alzheimer’s disease dementia
found a worsening of dementia when areas of dead tissue (infarcts) were present
in the brain, indicating that homocysteine contributes to dementia by inducing
vascular changes that result in insufficient blood flow to the brain and cell
death.9
DNA damage and cell death. Other events contribute to neuronal cell death by
homocysteine. Experiments in cell cultures show that homocysteine can directly
kill neurons of the hippocampus, the area of the brain associated with memory.
Cell death was induced by oxidative stress, DNA damage, and apoptosis.10 Such
events occurring in vivo would result in a deficit in cholinergic neurons and
faulty transmission of signals in the brain that characterize dementia.
Folate deficiency and loss of DNA repair. Homocysteine’s
damaging effects on DNA are worsened by folate deficiency. Studies show that
a lack of folate prevents the repair of DNA in hippocampus neurons following
exposure to homocysteine, resulting in the accumulation of DNA damage and
cell death. Investigators from the Laboratory of Neuroscience at the National
Institute on Aging in Baltimore, MD, found that a lack of folic acid rendered
hippocampus neurons vulnerable to death by amyloid beta peptide, a free radical
producing toxic molecule found in the brains of Alzheimer’s disease
patients. Thus, folate deficiency increases the toxicity of amyloid beta
peptide, and when occurring in vivo, could lead to accelerated neuronal cell
death and dementia.11 This was seen
in experimental mice that were genetically modified to have high levels of
amyloid beta peptide and kept on a folic acid-deficient diet. The mice showed
increased DNA damage and neurodegeneration in the hippocampus, further demonstrating
that folic acid deficiency sensitizes cells to oxidative damage induced by
amyloid beta peptide.11
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