Alzheimer’s
disease: The continuing search for treatments
and persistent hopes for prevention
(This
excerpt if from an article first printed
in the December 2003 issue of the Harvard Mental
Health Letter. For more information or
to order, please go to www.health.harvard.edu/mental.)
This part our progress report reviews ways in
which nutritional factors, cardiovascular disease,
blood sugar, and depression may influence Alzheimer’s
disease and how those associations may suggest
hope for prevention.
Homocysteine and B vitamins
Homocysteine is an amino acid (protein constituent)
contained in food and broken down in the body
by a process that relies on vitamin B 6, vitamin
B 12, and folic acid (folate). If that process
fails, homocysteine accumulates, raising the
risk for heart disease. The risk of cognitive
decline and dementia may also rise, although
evidence is conflicting. In the Framingham Heart
Study, people with the highest levels of homocysteine
were most likely to develop dementia within eight
years. But there is no evidence that B vitamins
or folate can prevent or reverse decline in Alzheimer’s
disease. In one current experiment, scientists
are depriving genetically vulnerable mice of
folate to observe changes in memory and homocysteine
levels.
Omega-3 fatty acids
These polyunsaturated fats are found mainly
in fish and in certain vegetable oils (especially
flaxseed oil). Supplements containing omega-3s
have been proposed as a treatment for depression
and bipolar disorder, and now it’s being
suggested that they can also help to prevent
or delay dementia. In a study that followed 800
people for four years, those who ate fish at
least once a week had a 60% lower risk of developing
dementia. The effect was independent of cardiovascular
disease and the consumption of vitamin E and
overall dietary fat. There are no controlled
studies on the effect of omega-3 fatty acids
in dementia.
The cardiovascular connection
Cardiovascular disease, stroke, and Alzheimer’s
disease may share some risk factors, including
high blood pressure and high levels of C-reactive
protein, which is associated with inflammation.
People who carry the E4 variant of apolipoprotein
E are more susceptible than average to heart
disease and stroke as well as to Alzheimer’s
disease. A Dutch study published in 2003 found
that silent strokes more than doubled the risk
of dementia, including Alzheimer’s. In
a reported six-year follow-up of people over
75, those with high systolic blood pressure had
a 50% greater than average risk of developing
Alzheimer’s.
A survey published in 2002 found that people
who took one type of antihypertensive drug, a
calcium-channel blocker, were 50% less likely
to develop either vascular dementia or Alzheimer’s
disease over a four-year period. No other blood
pressure drugs had this effect, so calcium-channel
blockers may have some unique action unrelated
to blood pressure — or patients who were
given these drugs may have been different in
some way that affected the risk of dementia.
Without controlled studies, there is still no
way to tell.
Cholesterol and statins
High levels of “bad” (LDL) cholesterol,
one of the risk factors for cardiovascular disease,
may also be a factor in Alzheimer’s disease.
The interaction of cholesterol with beta- amyloid
could contribute to neuronal tangles. Genetically
engineered mice with Alzheimer’s-like symptoms
have high levels of LDL cholesterol. A study
published in 2003 finds a correlation between
high LDL cholesterol and faster decline in Alzheimer’s
patients taking cholinesterase inhibitors. But
other research, including the Framingham Heart
Study, shows no link between Alzheimer’s
disease and blood levels of cholesterol or consumption
of saturated fats.
Scientists investigating this relationship are
interested in the effects of statins, the widely
prescribed cholesterol-lowering drugs. A meta-analysis
of seven surveys published in 2003 found that
people who took statins were 50% less likely
to develop Alzheimer’s disease. But, controlled
studies have been disappointing. Several clinical
trials have found that assorted statins have
no effect on the function of the aging brain,
and one study found no effect on the level of
beta-amyloid in the spinal fluid. Research continues.
Blood sugar and insulin
High levels of blood sugar and insulin resistance
may be associated with memory decline and atrophy
of the hippocampus. In type 2 diabetes, levels
of insulin rise because the body becomes less
sensitive to it and the pancreas produces more
in order to compensate. High concentrations of
insulin could raise the risk of Alzheimer’s
disease by hogging insulin-degrading enzyme — an
enzyme that also breaks down amyloid plaques.
Genetically engineered mice that lack this enzyme
develop Alzheimer’s-like symptoms and amyloid
plaques. Scientists are now feeding these mice
high-carbohydrate diets, which raise insulin
levels, to see how their condition is affected.
Meanwhile, some experts are proposing drugs that
lower insulin resistance as a possible treatment
for Alzheimer’s disease.
Except for cholinesterase inhibitors, all the
prevention and treatment methods discussed so
far are doubtful. Some of them have little more
backing than a speculative theory. In other cases
the research is at an early stage — experiments
only in cell cultures or animals. With the more
familiar drugs and dietary ingredients, the evidence
is conflicting, and controlled trials have been
mostly discouraging. However, newer approaches
hold more immediate promise.
Mental fitness
Physical exercise helps to prevent physical
deterioration. Could mental exercise prevent
intellectual deterioration, including dementia?
Learning and intellectual activity might forge
new connections in the brain and delay the disintegration
of its circuitry. A study published in 2003 in
the New England Journal of Medicine found
that in a group of people over 75, those who
were in the top third for leisure-time mental
activity — defined as reading; dancing;
or playing cards, board games, or musical instruments — had
a 63% lower risk for developing either Alzheimer’s
disease or vascular dementia than those in the
bottom third. The association was independent
of age, medical illness, and verbal IQ.
But it’s hard to tell how cause and effect
are related. People may stop reading or playing
cards simply because they no longer have the
capacity. In other words, what looks like intellectual
laziness could be an early symptom of dementia
rather than one of its causes. A long-term study
of Catholic nuns, priests, and monks found that
those with either a college education or a larger-than-average
head size (suggesting a relatively large brain)
were four times less likely than those with less
education or smaller brains to develop symptoms
of dementia at a given age — even though
their brains did not contain fewer amyloid plaques
and tangles. This finding supports the theory
that the appearance of dementia symptoms is delayed
by cognitive reserve — extra capacity for
compensatory brain activity. Reading or playing
chess in old age might be evidence of cognitive
reserve rather than a shield against dementia.
Depression and Alzheimer’s
The close relationship between depression and
Alzheimer’s disease is beginning to come
into clear view. In one study, nearly 50% of
patients with Alzheimer’s were found to
have had an episode of major depression during
their lives, and about a third developed major
depression after cognitive decline began. Depression
also occurs at a higher-than-average rate in
the relatives of people with Alzheimer’s
disease (see Harvard Mental Health Letter, September
2003). Psychiatrists have developed a diagnostic
test for depression in patients with Alzheimer’s.
And a placebo-controlled study in 2003 found
that the antidepressant drug sertraline (Zoloft)
was an effective treatment. It improved the behavior
of depressed Alzheimer’s patients and gave
caregivers more free time.
Caregivers
Caregivers themselves often need treatment — 60%
have some depressive symptoms, and one-third
develop major depression. It’s also been
found that they show changes in immune function
that may leave them more vulnerable to a variety
of chronic illnesses. In a study reported in
2003, six sessions of counseling and a support
group for caregivers delayed for a year the need
to place the Alzheimer’s patient in a nursing
home. Congress has been funding a National Family
Caregiver Support Program in which federal money
is allocated to demonstration programs in states
and local communities that offer counseling,
training, and support groups for people with
Alzheimer’s disease and their caregivers,
with special emphasis on the poor and minorities.
It may seem that there have been many more disappointments
than fulfilled hopes in the prevention, care,
and treatment of Alzheimer’s disease. But
anyone who is discouraged should consider how
much has been accomplished since the 1980s — the
remarkable discoveries about the pathology and
genetics of the disease, the use of brain scans,
the development of animal models with genetic
engineering, the understanding of mild cognitive
impairment, and promising treatment approaches.
As research proceeds in many directions, constantly
turning up new evidence and inspiring new ideas,
it continues to offer hope for winning the battle
against this enemy of the mind.
(This excerpt if from an article first printed
in the December 2003 issue of the Harvard
Mental Health Letter. For more information
or to order, please go to www.health.harvard.edu/mental.)
|
HOME
MY
CART
12
monthly issues
