|Scientists Report Important Step in Biomarker
Testing for Alzheimer's Disease
Scientists have made a significant step forward in developing
a test to help diagnose the early stages of Alzheimer's disease
sooner and more accurately by measuring two biomarkers — tau
and beta-amyloid proteins — in cerebrospinal fluid. In a
new report, researchers from the Alzheimer's Disease Neuroimaging
Initiative (ADNI) not only confirmed that certain changes in biomarker
levels in cerebrospinal fluid may signal the onset of mild Alzheimer's,
but also established a method and standard of testing for these
biomarkers. ADNI is a research partnership supported primarily
by the National Institute on Aging (NIA), part of the National
Institutes of Health, with private sector support through the Foundation
for NIH, seeking to find neuroimaging and biomarker tests that
can detect Alzheimer's disease progression and measure the effectiveness
of potential therapies.
These are the first cerebrospinal fluid biomarker findings to
be reported by ADNI, a $60-million, five-year research program
launched in 2004 to observe and track changes in some 800 older
people in the United States and Canada with normal cognition, mild
cognitive impairment (MCI) — a condition that often precedes
Alzheimer's — or the early stages of Alzheimer's. The ADNI
Biomarker Core at the University of Pennsylvania's School of Medicine
in Philadelphia, headed by Leslie M. Shaw, Ph.D., and John Q. Trojanowski,
MD., Ph.D., led the study, which is reported online March 17 in
the Annals of Neurology.
"Research indicates that Alzheimer's pathology causes changes
in the brain some 10 to 20 years before any symptoms appear," said
NIA Director Richard J. Hodes, M.D. "This work gives researchers
a systematic and reliable method to measure changes in cerebrospinal
fluid biomarkers that may herald the onset of Alzheimer's disease.
More research is needed to validate these findings, but this study
takes us one step closer to providing researchers and clinicians
with tools to detect and understand the very early signs of the
The researchers collected cerebrospinal fluid from 410 ADNI volunteers
at 56 different sites, tested the samples for the tau and beta-amyloid
protein biomarkers associated with Alzheimer's pathology, and then
retested the volunteers a year later to track changes in cognition.
The scientists also compared the ADNI cerebrospinal fluid samples
to those collected from an independent group of 56 people who were
later confirmed in autopsy to have had Alzheimer's and from 52
older people with normal cognition.
This comprehensive analysis allowed the scientists to systematically
confirm earlier studies on cerebrospinal fluid findings and to
develop biomarker profiles that may signal the onset of the disease.
Among their findings:
- Levels of beta-amyloid protein, in particular beta-amyloid
1-42, were lower among ADNI volunteers with MCI compared to those
with normal cognition, and lower still among those diagnosed
with mild Alzheimer's disease. Decreased levels of this biomarker
in the cerebrospinal fluid may indicate that this least soluble
form of amyloid is forming sticky plaques between neurons, a
hallmark of Alzheimer's.
- Levels of beta-amyloid 1-42 proved to be the most sensitive
biomarker, with an overall test accuracy rate of 87 percent in
detecting Alzheimer's pathology in the ADNI volunteers and in
people with autopsy-confirmed Alzheimer's.
- Levels of tau were higher among ADNI volunteers with MCI than
among people with normal cognition, and even higher among the
volunteers diagnosed with mild Alzheimer's disease. Tau, a protein
released by damaged and dying brain cells, can form tangles within
cells and may prevent neurons from communicating with each other.
- In addition to cerebrospinal fluid biomarkers levels, the researchers
factored in a known genetic risk factor for Alzheimer's disease — the
gene APOE-e4 — into their analysis. The gene occurs in
about 40 percent of all people who develop Alzheimer's at age
65 or later, but how it increases risk is not yet known. ADNI
volunteers with APOE-e4 genes, high levels of tau and low levels
of amyloid were most likely to have mild Alzheimer's.
The scientists noted that all 37 ADNI volunteers diagnosed with
MCI at the start of the study were documented as having probable
Alzheimer's disease a year later. That conversion could be predicted
by their cerebrospinal fluid biomarkers, since their baseline profiles
were similar to ADNI volunteers already diagnosed with the disease.
Conversely, three ADNI volunteers with MCI at the start of the
study, but whose cerebrospinal fluid biomarker levels were similar
to volunteers free of the disease, reverted back to normal cognition
by the end of the study.
"This effort may open the door to the discovery of an entire panel
of cerebrospinal fluid biomarkers that will not only predict those
at risk of developing Alzheimer's disease, but also reveal how
the disease is responding to therapies," said Neil Buckholtz,
Ph.D., of the NIA Division of Neuroscience. "Like all ADNI
results, these findings have been posted to a publicly accessible
database available to qualified researchers worldwide."
To date, more than 800 researchers have signed up for ADNI database
access. Investigators may apply for access through the database
Web site at www.loni.ucla.edu/ADNI.
In addition, qualified scientists may also ask for access to the
cerebrospinal fluid and blood samples. An application form is available
under the “Scientist Home Page” link at www.adni-info.org/.
In addition to the NIA, the ADNI public-private partnership includes
federal support from the National Institute for Biomedical Imaging
and Bioengineering, also part of NIH, and the participation of
the Food and Drug Administration. Private sector support comes
from pharmaceutical companies and other organizations through the
Foundation for NIH, which has raised more than $25 million from
both corporations and non-profits toward ADNI. Current private
sector funders include Abbott Laboratories, AstraZeneca AB, Bayer
Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical
Development, Elan Corporation, Genentech, General Electric Healthcare,
GlaxoSmithKline, Innogenetics, Johnson & Johnson, Eli Lilly and
Co., Inc., Merck & Co., Inc., Novartis AG, Pfizer Inc, F. Hoffmann-La
Roche, Schering-Plough, Synarc Inc., and Wyeth Research, as well
as non-profit partners the Alzheimer's Association and the Institute
for the Study of Aging.
The Foundation for the National Institutes of Health was established
by the United States Congress to support the mission of the National
Institutes of Health — improving health through scientific
discovery. The foundation identifies and develops opportunities
for innovative public-private partnerships involving industry,
academia, and the philanthropic community. A non-profit, 501(c)(3)
corporation, the Foundation raises private-sector funds for a broad
portfolio of unique programs that complement and enhance NIH priorities
and activities. The Foundation's Web site address is www.fnih.org.
The NIA leads the federal government effort conducting and supporting
research on the biomedical, social and behavioral issues of older
people. For more information on aging-related research and the NIA,
go to www.nia.nih.gov. The
NIA provides information on age-related cognitive change and neurodegenerative
disease specifically at its Alzheimer's Disease Education and Referral
(ADEAR) Center site at www.nia.nih.gov/Alzheimers.
To sign up for e-mail alerts about new findings or publications,
please visit either website.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.