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THE RACE AGAINST AN ALZHEIMER'S DISEASE EPIDEMIC
NEW YORK CITY—For much of the past century, investigators were confounded by Alzheimer’s disease. Now, research advances have placed us on the threshold of effectively treating, and perhaps even eradicating, the disease. “It’s hard for us to imagine,” commented Stephen T. DeKosky, MD, Professor and Interim Chair of the Department of Neurology and Director of the Alzheimer’s Disease Research Center at the University of Pittsburgh. “Ten years ago most neuropathologists actually felt there was nothing we could do to even treat the disease, much less figure out ways to prevent it.” But advances in medical science might not be enough, Dr. DeKosky cautioned in his address at the 2001 American Medical Association’s media briefing on Alzheimer’s disease. A combination of demographics, elevated health care costs, and an underestimation of the prevalence of the disease have left the United States facing an epidemic.
LONGEVITY
INCREASES THE RISK
Of the three major issues causing the Alzheimer’s disease crisis, Dr. DeKosky placed the most significance on the raw prevalence of the disease. The Baby Boomers, Dr. DeKosky said, “are going to be the healthiest cohort of people ever to hit their 70s and 80s and probably are going to live longer than people did before. They will not have, perhaps, as many comorbidities as people currently in their mid-70s to 80s have.” He credits this longevity to a trend in aggressive treatments for hypertension, cholesterol, and other age-related diseases and notes, ironically, that in respect to Alzheimer’s disease, “with the ability to live longer you extend the lifetime of the disease. The burden to the population will increase.”
According to Dr. DeKosky, those
between ages 65 and 70 have about a 2% to 3% prevalence of dementia.
This rate increases to around 20% for the 75- to 85-year-old age bracket
and expands to 30% to 47% for those older than 85 years. The current
population of more than four million octogenarians in America is expected to double
by 2030. It will triple by 2040, and it is expected to quintuple by the middle
of the next century. “So even if we take a low estimate and say one third
of people over 85 are demented, if you extrapolated that one third of these new
additions to the population will be demented, you can see why there is such an
imperative to find medications not just for treatment but also for prevention,”
Dr. DeKosky said.
SLOWLY
BUT SURELY—SURELY
TOO LATE?
The primary way to determine
effective preventive strategies for Alzheimer’s disease has been to implement
prevention trials. There are three key elements that must be considered, according
to Dr. DeKosky. “They’re big, they’re expensive, they take a long
time.”
The nature of these prevention
trials is a function of the fact that only 1% to 2% of the elderly population—perhaps
3% in the 85 and older group—converts to Alzheimer’s disease per
year. “So for every hundred normal people you enter into a trial, only one
person per year may ‘convert’ to Alzheimer’s disease. Thus if you’re
going to try a placebo against a preventive medication, you need to have enough
time go by and have enough people entered in the first place to be able to show
a statistical lowering of the number of people in the medication group who get
the disease. That’s why almost all of these prevention trials take thousands
of people and four, five, six years to do.”
This logistical issue has
contributed to the epidemic potential of Alzheimer’s disease. A more efficient
hope for prevention trials, Dr. DeKosky observed, might rest with those involving
mild cognitive impairment. Defined by isolated memory loss, mild cognitive impairment
is a transitional state for many, though not all, people on the road to “the
frank expression of the disease.” Dr. DeKosky pointed out that “we know
from studies such as the Religious Orders Study that many of these patients who
die with mild cognitive impairment have Alzheimer’s disease changes in their
brains.”
Dr. DeKosky admits that it is
difficult to tell in someone with the earliest symptoms of memory loss whether
the changes are simply benign, age-associated changes or whether they will worsen
and develop into Alzheimer’s disease. It is equally difficult to make a qualitative
distinction between worsening mild cognitive impairment and Alzheimer’s disease.
However, the statistical fact that about 15% of patients with mild cognitive
impairment convert to Alzheimer’s disease makes it a viable, and indeed a
necessary, field for prevention trials. “That’s why there’s a great
deal of emphasis being placed on trials of mild cognitive impairment, because
more events will occur per year if you can identify these people, which means
the studies can be done more quickly and obviously a lot less expensively,”
said Dr. DeKosky. “Most of these trials take two to three years.”
There are a number of treatment
trials under way, but Dr. DeKosky urges that even more must follow. Additionally,
funding must be made available to facilitate the immediate pursuit of treatments
for Alzheimer’s disease along multiple fronts at the same time. The enormous
cost of simultaneous prevention trials makes this proposition problematic, but,
according to Dr. DeKosky, multiple, simultaneous trials are absolutely essential
if researchers and clinicians are to have any hope of stemming the tide of Alzheimer’s
disease. “If the Boomers will start to get the disease in large numbers 10
years from now, stringing these studies together end to end will probably result
in us not having decent answers about prevention by the time the epidemic is upon
us.”
TREATMENT
TARGETS
Dr. DeKosky elaborated on the
nature and the targets of these prevention trials, observing that there is “an
emphasis on early detection as well as the ability to give medications.”
While early intervention remains
an optimistic hope, targets for therapies remain focused on the three major kinds
of pathology in the disorder: neuronal death, neurofibrillary tangles, and amyloid
accumulation.
The neurofibrillary tangles
“are a very difficult target,” according to Dr. DeKosky. “They
are worse than cataracts you get on the lens of the eye, and you know how we treat
cataracts. We don’t dissolve them with eyedrops; we simply take them out.
And we’re not going to do that to neurons. So one of the issues of the emerging
realities of protecting our population is finding ways of stopping these tangles
from forming. Because once done, they will not be undone.”
Amyloids—specifically
beta amyloid—represent what Dr. DeKosky calls “our most hopeful target.”
The question, Dr. DeKosky concluded, is “if you can quiet [the plaque] down
and just let the beta amyloid lie there, would you slow the clinical progression
of the disease?”
CURRENT
AND PROSPECTIVE THERAPIES
Therapies for all three of these
pathologies are either symptomatic medicines, nonspecific therapies, or specific
therapies. Symptomatic medicines include the three esterase inhibitors commonly
administered to patients with Alzheimer’s disease. Nonspecific therapies
are those “directed towards pathologic processes in the brain that we see
in Alzheimer’s disease that aren’t necessarily specific for Alzheimer’s
disease.” Dr. DeKosky cited nonsteroidal anti-inflammatory drugs and antioxidant
reagents such as vitamin E as “classic nonspecific therapies.” He added
that statins are also being tested “because there does appear to be a relationship
among cholesterol and deposition of beta amyloid.”
Specific therapies, which
Dr. DeKosky said “target the specific pathologic changes in Alzheimer’s
disease that generally don’t occur in other disorders, or at least aren’t
the centerpiece of those,” are in the early stages of development. They include
neurotrophins “that would stop neuronal cell death or stop the retraction
or slow withering of neuronal connections,” anti-neurofibrillar drugs, “which
will also be related to stopping [neurofibrillar tangles] early,” and “anti-amyloid
medications to stop the progression of that pathology.”
ARE
ANTI-AMYLOID DRUGS THE BEST BET?
Dr. DeKosky puts his greatest
hope for stopping the probable flood of Alzheimer’s disease on the anti-amyloid
medications. “This really is, I think, where the future is mortgaged for
us, in terms of being able to stop this disorder,” he said. In a map of a
hypothetical treatment, Dr. DeKosky explained that “if you could, you would
enhance the alpha secretase, stop the beta, stop the gamma, and for anything that
seeps through you’d use an antibody to sweep it out of the brain as fast
as you could.”
He pointed out that a productive animal model for the deposition of amyloid
has been made with transgenic mice that have been engineered with amyloid protein
precursor from humans. Experiments with these animals proved that “you could
actually interfere with amyloid deposition in the brain” in two ways.
The first is a protection
model. “If you immunize mice before they ever deposit the amyloid in their
brains, you can stop them from depositing in the brain,” Dr. DeKosky said.
A 1-year-old mouse that has the human mutated [amyloid protein precursor] gene
showed the expected deposition of amyloid plaque. An animal of the same age that
had been injected every six weeks from about age 6 weeks, had “virtually
no deposition of plaque in its brain [and] much less inflammation.”
The second model, a model
of treatment, showed that, with respect to 1-year-old animals that have already
developed plaque all over the brain, animals “begun with immunization at
12 months have not only not accumulated what they ought to have at 18 months but
in fact probably have decreased a bit of their deposition,” Dr. DeKosky said.
These demonstrations have led
to the first safety trials governing the use of such medications in humans. Phase
I trials are under way both for the anti-amyloid vaccine as well as for the suppression
of the gamma-secretase to stop the abnormal clippings from occurring. “Hopefully
we could stop the deposition,” Dr. DeKosky said, “with the idea that
if you could stop this cascade you could stop the disease from progressing, and
if you could start [treatment] early enough, you could prevent people from becoming
symptomatic.”
NR
—C.
Justin Romano
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