A Candidate Plasma Protein Classifier to Identify Alzheimer's Disease

Abstract

Biomarkers currently used in the aid for the diagnosis of Alzheimer's disease (AD) are cerebrospinal fluid (CSF) protein markers and brain neuroimaging markers. These biomarkers, however, either involve semi-invasive procedures or are costly to measure. Thus, AD biomarkers from more easily accessible body fluids, such as plasma, are very enticing. Using an aptamer-based proteomic technology, we profiled 1,129 plasma proteins of AD patients and non-demented control individuals. A 5-protein classifier for AD identification was constructed in the discovery study with excellent 10-fold cross-validation performance (90.1% sensitivity, 84.2% specificity, 87.9% accuracy, and AUC as 0.94). In an independent validation study, the classifier was applied and correctly predicted AD with 100.0% sensitivity, 80.0% specificity, and 90.0% accuracy, matching or outperforming the CSF Aβ42 and tau biomarkers whose performance were assessed in individual-matched CSF samples obtained at the same visit as plasma sample collection. Moreover, the classifier also correctly predicted mild cognitive impairment, 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 postmortem diagnosis, the 5-protein classifier appears to be a promising blood test to contribute diagnosis of AD.

Combined Plasma and Cerebrospinal Fluid Signature for the Prediction of Midterm Progression From Mild Cognitive Impairment to Alzheimer Disease

“…Recently, 2 candidate signatures of progression to AD were proposed. 50,51 These studies were, however, limited to the prediction of progression to AD 1 year before its clinical diagnosis. In addition to plasma biomarkers, CSF-based biomarkers may be particularly representative of the disease progression because CSF is in close contact with the central nervous system.…”

Biomarkers for the Early Detection and Progression of Alzheimer's Disease

“…A newly developed SOMAscan discovery-based platform was used to analyze 1129 plasma proteins simultaneously in blood samples from patients with AD and healthy controls [247]. In the discovery set, a 5-protein classifier (S100A9, CD84, CD226, AIF1, and ESAM) was identified that discriminated people with AD from healthy controls with a sensitivity and specificity of 90.0% and 84.2%, respectively, outperforming CSF tau and Aβ 42 markers from the same cases.…”

“…In the discovery set, a 5-protein classifier (S100A9, CD84, CD226, AIF1, and ESAM) was identified that discriminated people with AD from healthy controls with a sensitivity and specificity of 90.0% and 84.2%, respectively, outperforming CSF tau and Aβ 42 markers from the same cases. In a validation study, the classifier discriminated controls from individuals with MCI with 96.7% sensitivity and 80% specificity [247]. Finally, an unbiased mass spectrometric lipidomics approach was used to identify a plasma phospholipid panel that predicted phenoconversion to MCI or AD within a 2 to 3-year timeframe with > 90% accuracy [248].…”

Aβ and tau structure‐based biomarkers for a blood‐ and CSF‐based two‐step recruitment strategy to identify patients with dementia due to Alzheimer's disease

“…These techniques require either invasive lumbar punctures or expensive PET analyses, which rely on the use of radioactive compounds. Thus, there is a general agreement that a minimal-invasive, reliable, and cost-effective blood test is requested as a first screening funnel to identify individuals with high risk for AD [11][12][13][14][15]. To date, only few blood tests present the potential to detect AD [16][17][18][19].…”