Alzheimer's Diagnosis and the Role of Biomarkers

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 SOMAscan^TM 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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