Xuemei Zhao, Principal
Scientist Merck Research Laboratories
Alzheimer’s disease
(AD) is the most common form of dementia and it is increasingly prevalent in
people over 65 years old. In developed
countries, AD places a tremendous burden on individuals and society. To date, the cause and progression of the
disease are not fully understood.
Although symptomatic therapy has been approved, there is no agent
available to stop or reverse the disease.
Many therapeutic candidates are in development with some showing
promising results. Clinical diagnosis of
AD relies on characteristic neurological and neuropsychological features. A definite diagnosis of AD, however, can only
be made by examining the neuropathological hallmarks of the disease, amyloid
plaques and neurofibrillary tangles, at autopsy. Therefore, biomarkers that aid in the
diagnosis of AD would have great value in the development of AD therapeutics
and clinical practice.
Protein markers in cerebrospinal
fluid (CSF) and neuroimaging markers have been shown to contribute to the
diagnosis of AD. CSF protein biomarkers
include total tau, phosphorylated tau, and the 42 amino acid form of amyloid-b (Ab42). Some recently developed positron emission tomography (PET) agents for amyloid deposition imaging are the 11C
Pittsburgh Compound B (11C-PIB) and newer, FDA-approved amyloid
imaging agents such as Amyvid and Flutemetamol.
Other AD imaging modalities are atrophy on structural magnetic resonance
imaging (MRI), and hypometabolism on [18F]fluorodeoxyglucose (FDG)
PET. The validity of these biomarkers of
amyloid plaque deposition and neurodegeneration owing to AD is supported by
autopsy correlation studies.
Implementation of these markers in the clinic, however, is not ideal in
that CSF collection by lumbar puncture is a relatively invasive procedure and
PET/MRI measurements are expensive, facility restricted, and may be further
limited by personal conditions such as pacemakers. Therefore, identification of robust
biomarkers in an easily accessible body fluid would aid in the early detection
of the disease and facilitate development of disease-modifying agents.
We performed two independent studies,
discovery and validation, to identify AD markers by profiling proteins in human
plasma using the aptamer-based SOMAscanTM technology. Specifically, we aimed to identify markers
with better performance than the best-performing CSF markers, tau and Ab42, to discriminate AD from non-demented
controls. We constructed a 5-protein
classifier in the discovery study and demonstrated that the plasma protein
classifier allowed the prediction of AD with 100.0% sensitivity, 80.0% specificity,
and 90.0% accuracy in an independent validation study, matching or
outperforming CSF tau and Ab42. Individual-matched plasma and CSF samples
were obtained at the same visit, allowing direct comparison of diagnostic
performance between the plasma protein classifier and CSF protein biomarkers. Moreover, the classifier also correctly
predicted mild cognitive impairment (MCI), an early pre-dementia state of the
disease, with 96.7% sensitivity, 80.0% specificity, and 92.5% accuracy. These studies demonstrate that plasma
proteins could be used effectively and accurately to contribute to the clinical
diagnosis of AD. Although additional and
more diverse cohorts are needed for further validation of the robustness, including
the support of post mortem diagnosis, the 5-protein classifier appears to be a
promising blood test to contribute diagnosis of AD.
Learn more about Xuemei's work in identifying Alzheimer's disease.
You can hear more from Xuemei at this year's Bioassay and Bioanalytical Method Development event. Join us October 20-22 in Boston, MA. Download the agenda here to see what else is on tap.
SAVE $100. Register here and use code XP1969BLOG.
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