deep for the
roots of dementia
all facial tissues are Kleenex. Not all photocopiers are Xeroxes.
Not all adhesive bandages are Band-Aids. And not all dementias are
Alzheimer’s disease. Like the brand names that are virtually
synonymous with the products they represent, Alzheimer’s has
become the form of dementia that has greatest awareness in the public
definitely in the era where Alzheimer’s dementia rules the
day,” says Howard Crystal, MD, professor of neurology and
pathology at the State University of New York Downstate, Brooklyn.
To some extent,
this is understandable, since Alzheimer’s disease, or AD,
comprises about 70 percent of dementias. “Sometimes people
start thinking about Alzheimer’s and dementia as the same
thing,” Dr. Crystal says. “But they are not.”
Vascular disease contributes to an important fraction of dementia
cases as well, though that fraction is difficult to estimate.
among causes of dementia assumes greater urgency as basic research
begins to illuminate the biochemical pathology underlying common,
late-onset AD and as epidemiological and longitudinal cohort studies
attempt to define more precisely how vascular disease contributes
to dementia. Two critical practical benefits are expected from this
work: early diagnosis of dementias and more effective treatment.
advances in Alzheimer’s are really very interesting from the
point of view of delineating the pathogenesis of disease,”
says Barbara Crain, MD, PhD, associate professor of pathology at
Johns Hopkins Medical Institutions. Autosomal dominant mutations
in three genes—presenilin-1 (PS1), presenilin-2 (PS2), and
amyloid precursor protein (APP)—that cause early-onset AD
have been known for a number of years. Evidence is accumulating
that the processes these mutations affect also play an essential
role in the predominant sporadic cases.
three genes are intimately associated with the central AD pathology—
deposition of beta-amyloid [Abeta] in the brain,” Dr. Crain
says. “If we could figure out what their gene products were
doing, and then figure out how to block them, we could perhaps prevent
the formation of amyloid. To me, that is where we are heading in
terms of treatment.”
One prominent researcher in this area is Dennis Selkoe, MD, the
Coates professor of neurologic diseases at Harvard Medical School
and Brigham and Women’s Hospital. “PS1 and PS2 genes
are implicated in all forms of Alzheimer’s disease,”
Dr. Selkoe says. “That is because while they are mutated in
only a subset of early-onset cases of Alzheimer’s disease,
their gene products, the proteins presenilin-1 and presenilin-2,
are the active site of an enzyme called gamma-secretase, one of
two key enzymes that make Abeta throughout life. We believe that
without Abeta protein buildup, people wouldn’t get Alzheimer’s
about beta-secretase, the other enzyme that processes APP into Abeta,
have been made by Philip Wong, PhD, associate professor of pathology
and neuroscience at Johns Hopkins Medical Institutions, with professor
of neurology Donald Price, MD, and colleagues. They have proved
the enzyme called BACE-1 to be the beta-secretase, which also qualifies
as a major therapeutic target. “Knowing these enzymes,”
Dr. Wong says, “we could come up with drugs that would inhibit
their activity, inhibit production of Abeta protein, and decrease
AD is certainly “the gorilla in the room,” as Dr. Crystal
in the past few years more research has focused on cerebrovascular
disease as a cause of dementia, says David Desmond, PhD, associate
professor of neurology and pathology at SUNY Downstate.
in the elderly increases the risk of dementia by fourfold relative
to elders who don’t have stroke,” Dr. Desmond says.
“And in patients with stroke and dementia, cognitive decline
is more rapid even than in Alzheimer’s disease.”
also ongoing on the combination of cerebrovascular disease and AD.
“The Nun Study helped us to tease out the relative importance
of cerebrovascular disease and Alzheimer’s disease,”
Dr. Desmond says.
program to study vascular dementia, funded by the National Institute
of Aging, is headed by Helena Chui, MD, professor of neurology at
the University of Southern California, Los Angeles. “Our goal
is to improve diagnosis,” Dr. Chui says, “and to understand
how small-vessel disease, and brain injury resulting from small-vessel
disease, can lead to cognitive impairment by itself or, as commonly
occurs, in combination with Alzheimer’s.” The idea that
vascular pathology alone can cause dementia is “an assumption
that is still open to testing,” she says. “My bias is
that small-vessel disease can cause slowly progressive dementia
by itself. But that is still for us to prove.”
Ultimately, to make the greatest therapeutic impact on AD, early diagnosis
will be necessary. “We think there will be more effective medications
in the next decade or two,” says Marilyn Albert, PhD, director of the
Division of Cognitive Neuroscience in the Department of Neurology at JHMI. Dr.
Albert studies the transition from mild cognitive impairment to dementia. “We
want to intervene with these medications as early as possible. And likely they
will not be benign,” she says. “So we want to select the correct
patients. For that we need early and accurate diagnosis.” As experience
with cholinesterase inhibitors has shown, by the time AD becomes established,
it is difficult to affect the disease course substantially. “Right now
there is no single simple test that allows you to diagnose Alzheimer’s
disease at any point, much less early,” Dr. Albert says.
Diagnostic tests for analytes in cerebrospinal fluid were proposed
several years ago. However, Dr. Crain says, “Right now CSF
testing tells normals from demented patients as a group and, in
some studies, tells Alzheimer’s from non-Alzheimer’s
dementia. But there is a lot of overlap.”
of the activity of the protein products of the PS1 and PS2 genes
has shown that each functions as part of a four-protein complex
that executes the gamma-secretase function, which is to make the
second cut that releases the 42-amino acid Abeta peptide from its
770-amino acid precursor, APP. (The other three proteins in the
complex are called nicastrin, aph-1, and pen-2.) Gamma-secretase
is a novel aspartyl protease that cuts the intramembrane domain
of the transmembrane protein APP within the lipid layer—“a
strange place for a protease to cut a peptide bond,” Dr. Selkoe
says. Mutations in PS genes change the relative activity of gamma-secretase
on its two cleavage sites. Wild-type gamma-secretase cuts the 42-43
peptide bond 10 percent of the time and the 40-41 bond 90 percent
of the time. Mutated PS proteins cut the 42-43 bond 20 percent or
more of the time, so the amount of 42-amino acid Abeta—which
forms the first amyloid plaques—is doubled.
PS proteins produce Abeta throughout life, albeit at a low level.
“So presenilins are also players in the lifetime risk of sporadic
Alzheimer’s disease,” Dr. Selkoe says. How amyloid formation
is increased when PS genes are normal is not known, but it is clear
that a relatively small increase in the amount of Abeta can dramatically
increase the risk of AD.
it is likely for a few percent of common late-onset Alzheimer’s
disease that environmental factors will be found that change the
rate of the events [around APP],” Dr. Selkoe says. “But
I think a more common basis of late-onset disease will be genetic
mutations that alter the rate of these functions, especially clearance
of Abeta. My guess is that late-onset Alzheimer’s disease
is mostly a clearance failure.”
Dr. Selkoe studies
one enzyme that degrades Abeta, called insulin degrading enzyme,
or IDE. “Our colleagues Rudy Tanzi and Lars Bertram at MGH
[Massachusetts General Hospital] have found evidence of genetic
linkage and even allelic association between SNPs in IDE and late-onset
Alzheimer’s disease,” Dr. Selkoe says. “They have
indirect evidence implicating IDE, but they have not yet found any
single base change that tracks unequivocally with Alzheimer’s
work on beta-secretase, the enzyme that makes the first cut in the
formation of Abeta, confirmed that this activity resides in a protein
called BACE-1. “To prove that BACE-1 is really the key beta-secretase,
we had to genetically ablate it,” Dr. Wong says. So he and
his colleagues made a mouse in which the gene encoding BACE-1 was
absent. Nerve cells from the brain of this knockout mouse did not
make any Abeta peptide.
Dr. Wong and
his colleagues next worked with transgenic mice carrying mutated
PS or APP genes. These strains “recapitulate aspects of AD
pathology, including amyloid deposition,” Dr. Wong says. When
the BACE-1 gene was ablated in this model of AD, the mice no longer
showed amyloid deposition in their brains. “So if you could
find compounds that inhibit BACE-1, you would have a good chance
of preventing buildup of amyloid plaque in animal models, and we
think in humans as well,” Dr. Wong says. Pharmaceutical companies
are now screening for compounds that inhibit this enzyme.
compounds that inhibit presenilin might ameliorate plaque formation.
However, the gamma-secretase complex also processes proteins that
are essential in development, so inhibiting this activity might
have serious side effects. A particularly important developmental
protein processed by gamma-secretase, called Notch, is involved
in cell fate determination, especially in the embryo. “Notch
must be cut to regulate transcription of certain genes in the nucleus,”
Dr. Selkoe says. Even affecting Notch later in life could affect
such functions as hematopoesis. Could partial inhibition of gamma-secretase—by
20 to 30 percent—decrease Abeta deposition to a desirable
degree while allowing adequate Notch function? That’s an open
In this regard,
it is interesting that anti-inflammatory agents such as ibuprofen—which,
in epidemiological studies, are associated with a decreased risk
of AD—have recently been found by Edward Koo, MD, and Todd
Golde, MD, PhD, to act as gamma-secretase inhibitors. “Ibuprofen
can somehow affect presenilin and its ability to form the 42-43
peptide bond,” Dr. Selkoe says.
is also essential for functioning of the gamma-secretase complex,
one might try to reduce Abeta production by inhibiting nicastrin.
Theoretically, this maneuver would also inhibit Notch, with deleterious
effects on development. In fact, a nicastrin knockout mouse looks
like the Notch knockout phenotype, Dr. Wong says. However, nicastrin
remains a potential therapeutic target for AD: Mice heterozygous
for nicastrin develop normally. “Perhaps a compound that reduces
nicastrin activity by 50 percent would have a significant effect
on production of Abeta without a substantial impact on the Notch
signaling pathway,” Dr. Wong says.
Another strategy for reducing the amount of Abeta in plaques was
the anti-Alzheimer’s vaccine that was taken out of clinical
trials recently because it caused encephalitis. “Everyone
was quite disappointed when those early trials had to be stopped,”
Dr. Crain says. “It looked like the vaccine worked against
Alzheimer’s changes. Why it caused encephalitis in humans
but not in animals isn’t clear.” Dr. Crain believes
that the vaccine’s impact provides hope that this approach,
in an altered form, may eventually work.
Dr. Wong and
his colleagues are moving toward generating a mouse model in which
researchers could simulate a drug trial to define a therapeutic
time window for effective treatment. This model would have inducible
expression systems in which a gene of interest, such as BACE-1,
could be turned on or off. First, researchers would allow Abeta
to form in the brains of mice. “Then we would selectively
turn off the gene,” Dr. Wong says, “which would be analogous
to giving a drug to these animals, and watch to see if Abeta plaque
goes away.” What is the time window in which “therapy”
will be effective? When does plaque deposition become irreversible?
“This information can guide human trials,” Dr. Wong
says. Studies such as this are in their infancy and will take several
years to mature.
APP genes cluster in and around the Abeta peptide region. Mutations
in the N terminus region of Abeta promote increased cutting by beta-secretase,
while mutations at the C terminus increase cutting by gamma-secretase.
Thus, both types of mutations generate more Abeta peptide. A cluster
of mutations in the middle of the Abeta region is thought to increase
the amyloidogenic property, or aggregability, of Abeta peptide.
So in effect, all APP mutations can promote Abeta plaque formation.
is actually an anti-amyloidogenic enzyme: It cuts APP between the
cleavage sites of beta- and gamma-secretase, rendering Abeta peptide
have yet been found with mutations in either beta- or alpha-secretase.
Nor have humans been found with mutant forms of the three other
protein components of the gamma-secretase complex. The reasons for
this are not clear. On the flip side, Dr. Selkoe says, “there
are still quite a few genetic traits to be discovered. There are
any number of folks with a familial tendency to Alzheimer’s
disease in which none of the three proteins known to bear mutations
in AD is responsible.”
to mutations in PS1, PS2, and APP, the likelihood of having AD is
affected by one other known genetic trait: carrying the E4 allele
of the apolipoprotein E gene. Dr. Wong calls apoE “one of
the key genes involved in garden-variety AD.” People with
the E4 allele have an increased level of Abeta plaque in their brains.
“ApoE is a tendency or risk factor for AD, but is not determining
like the autosomal dominant mutations,” Dr. Crain says. ApoE
makes a protein that carries lipid around the body. The apoE protein
comes in three isoforms. Inheritance of the E4 allele increases
the risk of getting AD relative to the E2 and E3 alleles—two-
to fivefold for the heterozygous state and three- to 10-fold for
the homozygous state. “ApoE is an an important risk factor
for Alzheimer’s because it is relatively common,” Dr.
Selkoe says. Roughly 17 percent of Americans carry one apoE4 allele,
and about two percent are homozygous. Preliminary evidence suggests
that apoE also affects clearance of Abeta, perhaps binding and internalizing
it into cells, with the E4 allele having reduced clearance ability.
“Another theory is that apoE4 may somehow stabilize Abeta
in extracellular deposits, so you get more mature and less immature
or diffuse plaques,” Dr. Selkoe says.
disease did not always dominate thinking about
dementia. In fact, Dr. Crystal says, its current prominence reflects
a major turnaround. “Until the 1960s, most dementia cases
in older persons were thought to be due to vascular causes,”
he says. For about 60 years after Alois Alzheimer described his
eponymous disease in 1906, it was appreciated as a cause of dementia
but thought to be rare and to principally appear in people under
age 65. (Alzheimer’s three cases were 56, 56, and 61 years
old, much younger than our current notion of the typical AD patient.)
Clinico-pathological studies among patients in their 60s, 70s, and
80s in England in the 1960s, in which mental status tests were correlated
with brain autopsies, revealed the surprising fact that half of
people with dementia had only Alzheimer’s pathology postmortem.
Most of the other half had mixed Alzheimer’s as well as vascular
pathology. Overnight the number of people in the United States thought
to have AD went from a few thousand to perhaps 4 million. “Now
you could say this condition was a public health problem,”
Dr. Crystal says.
dementia is the poor cousin. Several studies from the mid-’70s
to mid-’90s sought to determine where vascular disease fits
into the dementia picture. In one, only six of 2,000 cases qualified
as pure vascular dementia on autopsy. However, any degree of Alzheimer’s
pathology was taken as the cause of the patient’s dementia.
“There are all different degrees of Alzheimer’s pathology,”
Dr. Crystal notes. And Alzheimer’s lesions evolve over 20
to 30 years. “If you have 10 years of lesions, is that enough
to make you demented?” he asks. “Perhaps not. But in
some studies that would be enough to say the dementia was not caused
by vascular lesions.” Clean cases of pure vascular disease
are rare. “How much does vascular disease contribute to cognitive
impairment in cases of mixed pathology?” Dr. Crystal says.
“No one knows.”
how many people with dementia have Alzheimer’s pathology only
or mixed Alzheimer’s-vascular dementia is “a very contentious
issue,” Dr. Desmond says. “Experts in cerebrovascular
disease believe that cerebrovascular disease is a major contributor
to dementia,” he adds. “Experts in the world of Alzheimer’s
believe cerebrovascular disease to be of minor importance.”
Before anyone can say how common vascular dementia is versus AD
and combined dementia, uniform criteria for cerebrovascular disease
as a cause of dementia are needed.
Dr. Desmond conducted a large epidemiologic study to evaluate the
contribution of CVD to dementia. He recruited more than 500 patients
who were at least 60 years old and admitted with ischemic stroke,
evaluated them at three months, then performed annual tests of cognitive
abilities and functional independence. At three months after stroke,
26.3 percent of patients met the criteria for dementia. Among patients
who were not experiencing dementia at three months, new dementia
was diagnosed in 72 (21.6 percent) over five to 10 years of followup.
“In this study, ischemic stroke was a very potent risk factor
for delayed dementia,” Dr. Desmond says. “I think we
can generalize that finding to people who experience stroke at an
were not done in this study. However, Dr. Desmond speculates that
some patients had Alzheimer’s changes—a reasonable inference
given the age of the cohort—and that some late dementia was
due to mixed neuropathology.
He cites data
from the Nun Study as evidence. A cohort of Catholic nuns was recruited
and followed with serial measures of cognitive function. Autopsies
were performed on those who died. Among nuns who met the neuropathological
criteria for AD, those who had suffered strokes that damaged important
parts of the brain, such as the thalamus, had dramatically worse
performance on cognitive tests than nuns who simply had Alzheimer’s
pathology at autopsy. “Perhaps silent strokes or infarcts
increase the risk or severity of dementia,” Dr. Desmond suggests.
How these two
conditions might interact is a focus of study. Dr. Desmond raises
hypotheses. Perhaps a person has a predisposition to AD and then
experiences a stroke, which may initiate the onset of Alzheimer’s.
“If stroke did not occur, would that person’s decline
to Alzheimer’s disease have begun?” he asks. “Can
stroke unmask Alzheimer’s disease?” Another possibility
is that a person with AD is declining slowly and stroke accelerates
vascular disease can impair cognitive functioning,” Dr. Crain
says. And autopsies frequently show small vascular lesions in people
with dementia. “If a patient has Alzheimer’s lesions
that are not enough to cause dementia, and on top of that vascular
lesions develop that also would not be enough to cause dementia,
can you get additive effects from that mixed pathology?” she
asks. “Proving that would be extremely difficult.”
related to the importance of mixed pathology have been made in people
with risk factors for vascular disease. Dr. Crystal cites studies
in which tens of thousands of people with hypertension took neuropsychological
tests. “You find that hypertensives do a little worse than
nonhypertensives over time,” he says. “The difference
is very subtle. You wouldn’t notice it in individuals, but
you do see it in group studies.” On imaging, people with hypertension
or diabetes have more cortical atrophy, more white matter disease,
and less white matter volume. Again, differences are small. In Dr.
Desmond’s study, diabetes increased the risk of dementia.
“This has also been found in other cohorts of stroke patients,”
Along this same
line, epidemiological studies have, after controlling for many AD
risk factors, showed that people taking statins are less likely
to have Alzheimer’s disease. Dr. Crystal calls the evidence
that statins reduce the risk of Alzheimer’s “very compelling.”
The Alzheimer’s Disease Cooperative Study is conducting prospective
studies of statins among people with AD.
Dr. Crystal says, it appears from epidemiological studies that patients
with vascular diseases, including coronary artery disease, do suffer
more dementia. “My first response,” he says, “is
that they have vascular dementia, not Alzheimer’s dementia.
But the data are compelling that they do have true Alzheimer’s
disease.” It is not clear why this is so. However, Dr. Crystal
emphasizes, “that makes it more important to be able to untangle
whether a given case of dementia is Alzheimer’s or vascular.”
care of patients, we have to know what we are treating,” Dr.
Desmond adds. Dementia is not a disease; it is an outcome of a variety
of diseases. “In an individual, we need to know whether to
treat Alzheimer’s disease or cerebrovascular disease or Lewy
body disease, or perhaps to treat more than one etiology,”
he says. Treating risk factors for CVD can dramatically reduce the
incidence of stroke and possibly of dementia.
ways of estimating the contribution of vascular disease
to dementia, Dr. Chui, along with Harry Vinters, MD, professor of
neuropathology at UCLA, and others, has enrolled a cohort of people
with cerebral small-vessel disease, AD, or mixed pathology and a
group of normal age-matched controls. Cognitive testing is repeated
annually and MRI scans biennially. Imaging hyperintensity on T2-weighted
sequences in deep white matter and deep gray matter is used as a
surrogate for vascular disease. Imaging changes in the hippocampal
region serve as an Alzheimer’s surrogate. All 570 subjects
will be followed to death, and brain autopsy will be performed to
detect AD pathology and estimate the extent of vascular injury.
A number of valuable observations have already emerged. The initial
measure of small-vessel disease—a single score—“doesn’t
correlate very well” with cognitive dysfunction, Dr. Chui
says. Alzheimer’s pathology does explain cognitive impairment.
On imaging, cognitive decline is fairly well predicted by hippocampal
plus cortical atrophy, not so much hyperintensity but overall severity
of gray matter pathology. “We have also found that cortical
gray matter atrophy is not specific for Alzheimer’s,”
Dr. Chui says. Some cases of pure vascular disease show cortical
atrophy of the whole surface area. “This is surprising,”
Dr. Chui says. “It was previously thought that general atrophy
is related to Alzheimer’s and that vascular disease only causes
focal atrophy. But that is not what we have found so far.”
Dr. Chui says
that one distinctive finding in the 45 people who have gone to autopsy
so far is that hippocampal atrophy, an important correlate of cognitive
impairment, cannot be completely explained by AD. A subset—about
10 percent—have hippocampal sclerosis (no plaques or tangles),
both focally and, in some cases, extending over most of the hippocampus.
“That also thickens the plot,” Dr. Chui says. What causes
hippocampal sclerosis is controversial. “Perhaps small-vessel
injury,” Dr. Chui speculates.
that some experts say vascular pathology causes dementia only in
rare Binswanger-type cases (deep white matter pathology). “In
our 45 cases, what I have appreciated is that probably the truth
is going to be less extreme,” Dr. Chui says. “A lot
of those cases have some early Alzheimer’s and some vascular
disease, and the two are working additively.”
To improve early
diagnosis, Dr. Albert and other researchers are following people
who have mild cognitive impairment, or MCI, but who do not yet have
dementia. “We have had some success in predicting outcomes,”
she says. “But I think what is increasingly clear is that
each research group is looking at a slightly different cohort based
on referral patterns and selection method.” Some groups are
looking at people 80 and older, while others take only people who
have been referred because they complain of memory loss or a primary
care physician notices cognitive difficulty. So different research
groups are studying people with differing degrees of severity who
are further from or closer to the endpoint—conversion to dementia.
“You want people with a higher probability of converting,”
Dr. Albert says, “especially if you are testing medications.”
However, taking people too close to conversion
means you won’t get useful predictors for those in the early
stages of cognitive decline.
is that there is no fixed definition of MCI. For an ongoing drug
study, the Alzheimer’s Disease Cooperative Study defined MCI
fairly narrowly: people who reported memory problems themselves
plus a collateral source to confirm progressive difficulty with
memory. “They are getting a conversion rate of 15 percent
per year,” Dr. Albert says, “but those people have an
awful lot of trouble when they start out.” If you don’t
define MCI so strictly, you get large numbers of people who don’t
progress in a short time and large numbers with normal aging who
remain stable. “It makes sense to have subjects with a range
of difficulty,” Dr. Albert says, “to represent a range
of pathological change in the brain.” Dr. Albert and her former
colleagues in Boston formed such a cohort, and the conversion rate
has been relatively low. “We started 10 years ago,”
she says. “At that time I don’t think anyone understood
that MCI has as broad a range as it has turned out to have.”
However, this has turned out to be an advantage, Dr. Albert believes.
“We are now in a good position, because we have persons who
have mild MCI and people who are impaired, and we can study the
whole spectrum of severity.”
have proved to be good predictors at the cohort level of who will
develop AD. “The most powerful memory measures are those that
are somewhat difficult in our hands,” Dr. Albert says. “We
have found that measures of new learning that require verbal information
are particularly sensitive. However, these measures turn out to
be exceedingly difficult from the perspective of being accurate
on an individual basis.” As a result, memory tests alone are
inadequate. “Even with tests of executive function, we still
have a long way to go,” Dr. Albert says.
are useful at increasing accuracy, presumably because they measure
not only mental function but also brain lesions related to that
function. Anatomic imaging provides good agreement with conversion.
“If you measure the volume of regions that are part of the
medial temporal lobe memory system,” Dr. Albert says, “you
improve your accuracy in predicting who will develop Alzheimer’s.”
Some apparently crucial areas are the entorhinal cortex, the hippocampus,
and other regions such as the superior temporal sulcus. Plaques
can be imaged in persons with AD, but they can’t yet be imaged
in those with MCI to predict development of disease. With functional
imaging, glucose metabolism has been seen to be decreased in those
with the apoE4 allele. “It is unclear how that relates to
diagnosis,” Dr. Albert says.
Institute of Aging is trying to organize a large study with several
centers that would follow normal people, those with MCI, and AD
patients with imaging measures, as well as biological measures,
to look for a relationship between these parameters and development
or progression of disease. “Drug companies are very interested
in using imaging or other yet to be identified biomarkers to shorten
the time over which they would have to follow people to know if
a drug is effective,” Dr. Albert says.
agrees: “Identifying Alzheimer’s early remains a hot
issue.” He thinks that expanding MCI to nonmemory impairment
would be useful. “People with cerebrovascular disease often
present with impairment in executive functions—initiation
of behavior, decisionmaking, inhibition of behavior—that are
less concrete than memory or language,” he says. “Criteria
that look for mild cognitive impairment in any domain would be most
While many issues
surrounding dementia remain unsettled, our knowledge has advanced substantially
over the past several years. Under the probing of contemporary molecular genetic
techniques, the neuropathology of AD, which initially looked like an impenetrable
tangle, has yielded several crucial secrets. Therapeutic trials with specifically
targeted drugs are underway. A greater understanding of the relevance of vascular
dementia has emerged, and the question of the significance of mixed pathology
dementia is being directly addressed. Longitudinal studies are seeking the keys
to detecting which people with MCI will progress to dementia. Combined, these
initiatives may lead to optimal application of potent anti-dementia therapy, so
that late-life cognitive decline will become a manageable condition.
William Check is a medical writer in Wilmette, Ill.