Alzheimer's, Dementia & Mental Health
Researchers Identify Genetic Marker of Most
Aggressive Alzheimer’s Disease
New research points to how rapidly
Alzheimer’s patients develop full-blown dementia after diagnosis - this
genetic marker tends to indicate higher tau protein levels
By Jim Dryden, Washington University
Sept. 17, 2010 - An international team of
Alzheimer’s disease experts, led by Washington University School of
Medicine in St. Louis, has uncovered a gene variation that appears to
predict the rate at which Alzheimer’s disease will progress.
The investigators report their findings online in
the journal Public Library of Science (PLoS) Genetics.
Whereas previous studies have focused on factors
that influence the risk for Alzheimer’s, the new research points to a
way to determine how rapidly Alzheimer’s patients may develop full-blown
dementia after their diagnosis.
The investigators studied 846 patients with
elevated levels of a protein called tau in their cerebrospinal fluid
(CSF). Recent studies have found that the presence of a particular form
of the tau protein in the CSF is an indicator of Alzheimer’s disease.
The researchers also looked at single DNA
variations in the patients and identified a genetic marker linked to
elevated tau levels. That marker turned out to be associated with rapid
progression of Alzheimer’s disease.
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Alison M. Goate |
“People who carry this genetic marker tend to have
higher tau levels at any given stage of the disease than individuals
without it,” says senior investigator Alison M. Goate, DPhil., the
Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry.
“Until now, most studies of genetic risks
associated with Alzheimer’s disease have looked at the risk of
developing the disease, not the speed at which you will progress once
you have it. The genetic marker we’ve identified deals with
progression.”
For many patients and their families, that
information may be more useful than the knowledge that a person may be
developing Alzheimer’s damage in the brain even if that individual
hasn’t yet developed clinical symptoms, according to Goate.
Damage from the disease can be present for years
before symptoms appear. But this study suggests that elevated tau,
combined with the genetic marker, could be a sign that clinical symptoms
may quickly advance from mild impairment to severe dementia.
The study advances recent research that found it
was possible to diagnose Alzheimer’s disease, even in patients with no
clinical symptoms, by measuring levels of the amyloid beta protein in
the CSF. A-beta makes up the senile plaques that form in the brains of
Alzheimer’s patients, but it turns out that low levels of A-beta in the
CSF predict the presence of Alzheimer’s pathology in the brain.
Meanwhile, the tau protein collects in the other
abnormal brain structures that characterize the illness, called
neurofibrillary tangles. The tangles cause brain cells to die, and when
those cells die, tau is released into the CSF. So just as low A-beta
levels in the CSF are associated with Alzheimer’s disease, elevated tau
levels also indicate the presence of disease.
“Tau also can be released in stroke patients or
those with other types of brain injuries,” says first author Carlos
Cruchaga, PhD. “However, a particular form of tau is specific to
Alzheimer’s. It’s a phosphorylated form of the protein called ptau.
Other neurodegenerative conditions, like Parkinson’s disease, don’t
produce elevated ptau in the CSF. It’s only found in Alzheimer’s
disease.”
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Carlos Cruchaga |
Cruchaga, an assistant professor of psychiatry at
Washington University, says there was no association between ptau and
overall Alzheimer’s disease risk or age of onset for Alzheimer’s
patients, but there was a significant association between a variant of a
gene that plays a role in modifying the tau protein, ptau levels in the
CSF and the rate at which the disease progressed.
“We have looked at data from three separate,
international studies, and in all three, we found the same association,”
Cruchaga says. “So we are confident that it is real and that this gene
variant is associated with progression in Alzheimer’s disease.”
He says the genetic finding, combined with the
ability to measure ptau in the CSF may mean that if drugs could inhibit
the protein’s accumulation in the fluid, it might prevent or delay some
of the devastation associated with Alzheimer’s disease.
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“If we could somehow decrease tau pathology in
those individuals who also have low levels of A-beta in the CSF, we
might be able to slow the progression of the disease,” Cruchaga says.
Goate says the findings might initially be most
useful in the design of clinical trials. If researchers knew in advance
that particular study patients were going to progress at a rapid rate,
they could better evaluate the effects of drugs designed to slow the
progression of Alzheimer’s disease.
“I think that if the drug target is A-beta, then
treatment really needs to begin even before someone develops symptoms,”
Goate says. “In contrast, since most of the changes in tau occur after
someone already has symptoms, it may be possible to target that pathway
to slow progression of the disease, by interfering with the actions of
the tau protein.”
Notes:
This work was supported by grants from AstraZeneca,
National Institute on Aging, Barnes-Jewish Hospital Foundation, Ford
Foundation, Department of Veterans Affairs. Carlos Cruchaga has a
fellowship from “Fundacion Alfonso Martin Escudero.”
This work is also pending a patent filed by
Washington University in St. Louis, in which C. Cruchaga, AM Goate, DM
Holtzman and A. Fagan are named as inventors. The patent is currently
under option to AstraZeneca Pharmaceuticals LP. Goate and Holtzman were
consultants for AstraZeneca Pharmaceuticals LP in 2008/2009.
Washington University School of Medicine’s 2,100
employed and volunteer faculty physicians also are the medical staff of
Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine
is one of the leading medical research, teaching and patient care
institutions in the nation, currently ranked fourth in the nation by
U.S. News & World Report. Through its affiliations with Barnes-Jewish
and St. Louis Children's hospitals, the School of Medicine is linked to
BJC HealthCare.
Source: Cruchaga C, et al. SNPs association with
cerebrospinal fluid phospho-tau levels influence rate of decline in
Alzheimer’s disease. PLoS Genetics, vol. 6 (9). Sept. 16, 2010.
www.plosgenetics.org
