Promising Blood Biomarkers for Clinical Use in Alzheimer's Disease: A Focused Update

Abstract

Alzheimer's disease (AD) is the most-common cause of neurodegenerative dementia, and it is characterized by abnormal amyloid and tau accumulation, which indicates neurodegeneration. AD has mostly been diagnosed clinically. However, ligand-specific positron emission tomography (PET) imaging, such as amyloid PET, and cerebrospinal fluid (CSF) biomarkers are needed to accurately diagnose AD, since they supplement the shortcomings of clinical diagnoses. Using biomarkers that represent the pathology of AD is essential (particularly when disease-modifying treatment is available) to identify the corresponding pathology of targeted therapy and for monitoring the treatment response. Although imaging and CSF biomarkers are useful, their widespread use is restricted by their high cost and the discomfort during the lumbar puncture, respectively. Recent advances in AD blood biomarkers shed light on their future use for clinical purposes. The amyloid β (Aβ)42/Aβ40 ratio and the concentrations of phosphorylated tau at threonine 181 and at threonine 217, and of neurofilament light in the blood were found to represent the pathology of Aβ, tau, and neurodegeneration in the brain when using automatic electrochemiluminescence technologies, single-molecule arrays, immunoprecipitation coupled with mass spectrometry, etc. These blood biomarkers are imminently expected to be incorporated into clinical practice to predict, diagnose, and determine the stage of AD. In this review we focus on advancements in the measurement technologies for blood biomarkers and the promising biomarkers that are approaching clinical application. We also discuss the current limitations, the needed further investigations, and the perspectives on their use.

Keywords: Alzheimer's disease; biomarker; blood; diagnosis; precision.

Fig. 1. Ultrasensitive techniques for measuring blood biomarkers. ^*Additional step for stable isotope spiking absolute quantitation to improve amyloid β (Aβ) peptide quantification using isotope-labeled Aβ peptide at a specified concentration. Ab, antibody; B, biotin; ECL, electrochemiluminescence; IMR, immunomagnetic reduction; IP-MS, immunoprecipitation coupled with mass spectrometry; LC, liquid chromatography; M, magnetic; MS, mass spectrometry; SIMOA, single-molecule array; T, tag.

Fig. 2. Current limitations, suggested solutions, and possible clinical applications of blood biomarkers.