In a new
study, ASU-Banner NDRC researcher Paul Coleman and his colleagues at ASU, Mayo
Clinic, University of Rochester, Banner Alzheimer Institute and Barrow
Neurological Institute describe a blood test to detect Alzheimer's disease at a
pre-symptomatic state. Credit: Jason Drees for the Biodesign institute
According
to Paul Coleman, an Alzheimer's researcher at the ASU-Banner Neurodegenerative
Disease Research Center (NDRC), one of the greatest difficulties plaguing
efforts to find effective treatments for Alzheimer's is the enormous lag
between the disease's inception and the appearance of clinical symptoms
In a new study, Coleman and his
colleagues demonstrate the promise of an early blood test for Alzheimer's disease. The results
suggest that Alzheimer's can be detected even before the onset of symptoms in
persons at genetic risk for Alzheimer's disease.
In addition to the NDRC, study
collaborators include ASU, the Mayo Clinic, University of Rochester, Banner
Alzheimer Institute and Barrow Neurological Institute.
The new method
successfully distinguished between Alzheimer's, Parkinson's and healthy
controls, indicating that the test does not simply identify general phenomena
of neurodegeneration but is able to pick out AD from other degenerative brain
conditions.
"What we've done
in our paper is to replicate our own work multiple times with different
populations and even using different technologies," Coleman says. "We
also presented data showing the ability to detect people at risk of a future
diagnosis for Alzheimer's disease."
The method
accomplishes this feat by examining white blood
cells or leucocytes.
Here, segments of RNA known as transcripts—derived from specific DNA genes—hold
vital clues regarding health.
The study was
recently published in the journal Neurobiology
of Aging.
Hidden menace
Alzheimer's disease
continues its pitiless ascent. The illness afflicts 11 percent of those 65 or
older, with the figure soaring to 45 percent for people over 85. Current trends
predict some 14 million Americans will be afflicted with the disease by
mid-century at a towering cost of a trillion dollars.
Along its path of
destruction, Alzheimer's tears out its victim's memory, reasoning capacity and
personal identity, necessitating around-the-clock care, before death eventually
ensues. The crippling toll of the disease on patients, family and society at
large makes it a global health crisis of frightening proportions.
Researchers now know
that by the time the first outward manifestations of Alzheimer's appear, in the
form of confusion, memory loss and other classic hallmarks, Alzheimer's has
been ravaging the brain for decades. If the disease could be identified much
earlier—close to its origin—there is hope that perhaps it could be slowed or
even halted in its tracks.
Given the vital need
for a safe and reliable early diagnostic for Alzheimer's, many previous efforts
have taken aim at the problem. Ideally, such a method should be appropriate for
primary care settings, allowing a broad swath of the public to be accurately
and regularly tested.
Until now, however,
efforts to develop a reliable early diagnostic for Alzheimer's have run
aground. Further, the accuracy of diagnosis even after the disease has entered
its clinical phase, remains poor.
Signposts
of disorder
It has
long been known that Alzheimer's produces changes in the brain, which can
stimulate genes relating to conditions like stress and inflammation. Expression
of these genes appears in the blood in the form of specific RNA transcripts.
The
research results clearly demonstrate that these RNA transcripts can be combined
into a potent early diagnostic or biomarker, able to distinguish normal
patients from those with Alzheimer's or Parkinson's disease and—most
importantly— make accurate predictions about patients at risk for future
development of Alzheimer's disease.
The
diagnostic precision of the new test is significant. Existing diagnostic
screening results for known AD cases (identified through clinical and
neuropathological factors), showed diagnostic sensitivity was between 71
percent and 87 percent while specificity ranged from 44 percent to 70 percent.
(In medical diagnosis, sensitivity is the ability of a test to correctly
identify those with the disease, known as the true positive rate, whereas
specificity refers to the ability of the test to correctly identify those
without the disease or the true negative rate.)
Such
diagnoses are typically conducted in specialized facilities devoted to the
study of Alzheimer's. As the authors note, the accuracy of standard diagnosis
falls significantly in primary care settings. The result is that Alzheimer's is
generally detected very late in the disease process, if it is correctly
identified at all—a blueprint for treatment failure, because the illness has
already irreparably damaged the brain. The high rate of misdiagnosis leads to
frequently unnecessary and ineffective treatment.
Disease
in the cross-hairs
In a
fresh approach, the authors identify RNA transcripts in blood using two
different RNA-analysis techniques, known as cDNA array and reverse
transcriptase polymerase chain reaction (RT-PCR). Results of the two methods
were in close agreement and were further shown to be replicable across multiple
sample populations. This allowed the researchers to design a consistent suite
of transcripts that could be used to diagnose the disease. This multivariate
analysis demonstrated impressive accuracy in a number of critical experiments
described in the new paper.
The study
divides 177 blood and 27 post-mortem brain samples into several groups,
establishing that careful analysis of RNA transcripts in blood samples has the
ability to distinguish early clinical AD, Parkinson's disease (PD), and
cognitively healthy patients. It can accurately identify those carrying two
copies of the APOE4 gene—known to be a severe risk factor for developing
Alzheimer's. Transcript screening was also used to identify those at risk for
future cognitive impairment due to having at least one direct relative with AD.
The study
reveals that both cDNA and RT-PCR methods managed to distinguish probable AD
from normal controls with an accuracy of 93.8 percent, using just 5 RNA
transcripts for the test. As the authors note, the blood test's' accuracy may
be even higher as some of the "false positives"—healthy cases
mischaracterized as AD—may be from subjects who are actually positive for
pre-symptomatic manifestations of Alzheimer's.
Assessing
future risk
The
results demonstrate that multivariate analysis of transcripts in blood samples
provide an accurate and minimally invasive strategy for diagnosis of AD and
early detection of AD risk. Further, the results were consistent with
examination of the same transcripts identified in the post-mortem brains of
subjects with Alzheimer's compared with those diagnosed with Parkinson's
disease and with normal controls. (The brain samples, obtained through the
Banner Sun Health Research Institute, were taken from a region known to be
vulnerable to the most devastating effects of Alzheimer's.)
In
addition to RNA transcripts linked with inflammation and stress, the study
examines a series of epigenetic transcripts—RNA sequences that have undergone
post-transcriptional modification. Results again found a strong correlation
between the presence of these epigenetic markers and AD, implying they may also
provide a compelling diagnostic tool.
Future
refinements should sharpen the method's ability to accurately identify
Alzheimer's disease at an early stage—prior to the onset of clinical symptoms—
in a primary care setting, with just a simple blood extraction. Efforts to
conduct long term longitudinal studies and hunt for additional diagnostic
transcripts should eventually be combined with testing of new therapeutics
aimed at early intervention.
Intriguingly,
one or more of the many existing drugs for Alzheimer's which have failed in
clinical trials, may actually succeed in slowing or arresting Alzheimer's if
they can be delivered early enough in the disease process. Further, trials for
new drugs targeting at-risk patients can be ramped up significantly if a
simple, non-invasive blood test can replace costly imaging like PET scan.
The new early diagnostic therefore represents a
promising milestone in the war on
Alzheimer's disease.
https://medicalxpress.com/news/2017-08-early-alzheimer.html
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