Development of Alzheimer's Disease Biomarkers: From CSF- to Blood-Based Biomarkers

Abstract

In the 115 years since the discovery of Alzheimer's disease (AD), our knowledge, diagnosis, and therapeutics have significantly improved. Biomarkers are the primary tools for clinical research, diagnostics, and therapeutic monitoring in clinical trials. They provide much insightful information, and while they are not clinically used routinely, they help us to understand the mechanisms of this disease. This review charts the journey of AD biomarker discovery and development from cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (p-tau) biomarkers and imaging technologies to the next generation of biomarkers. We also discuss advanced high-sensitivity assay platforms for CSF Aβ42, T-tau, p-tau, and blood analysis. The recently proposed Aβ deposition/tau biomarker/neurodegeneration or neuronal injury (ATN) scheme might facilitate the definition of the biological status underpinning AD and offer a common language among researchers across biochemical biomarkers and imaging. Moreover, we highlight blood-based biomarkers for AD that offer a scalable alternative to CSF biomarkers through cost-saving and reduced invasiveness, and may provide an understanding of disease initiation and development. We discuss different groups of blood-based biomarker candidates, their advantages and limitations, and paths forward, from identification and analysis to clinical validation. The development of valid blood-based biomarkers may facilitate the implementation of future AD therapeutics and diagnostics.

Keywords: Alzheimer’s biomarker; amyloid-beta; blood-based biomarker; cerebrospinal fluid; clinical trial; tau.

Figure 1

Biomarkers and changes in spatiotemporal pattern of Aβ and NFT deposit during disease cascade. Abnormality in CSF Aβ42 and Aβ-PET (‘A’ abnormality) are biomarkers in pre-clinical stage, followed by abnormality in CSF p-tau or Tau-PET and ‘N’ abnormality (increased CSF T-tau and hippocampal atrophy).

Figure 2

Schematic summarizes the milestones of Alzheimer’s disease biomarkers evolute during the past century. In 1984, the first release of criteria for the clinical diagnosis of AD (NINCDS-ADRDA criteria) was published, and a definitive diagnosis of AD can be achieved only by the detection of Aβ plaques and NFT by autopsy. Subsequently, brain imaging technologies to detect amyloid accumulation in the brain using various PET ligands bound to amyloid plaque have emerged, and more recently tau PET has been introduced. Later, in 2011, the NIA-AA recommended diagnostic guidelines for non-symptomatic (i.e., preclinical) and symptomatic (i.e., MCI and dementia) stages. The recent new NIA-AA, updated in 2018, revised the diagnostic criteria for research and provided the new diagnostic approach based on the ATN classification system for the research framework. There are several molecular changes from neuron and glial cells (e.g., astrocyte and microglia) associated with CSF and/or blood biomarkers. If clinical evidence of the glial biomarkers for AD diagnosis becomes valid, the glial cell-derived biomarkers can contribute to clarifying the ATN classification in the future. Up-to-date blood-based biomarkers have been focused on and promised as new AD biomarkers. The PET images from [36,37] are used with permission from the publishers. NFT; neurofibrillary tangles, GFAP; Glial fibrillary acidic protein, CSF; Cerebrospinal fluid, PET; positron emission tomography; FDG-PET; fluorodeoxyglucose positron emission tomography, MCI; mild cognitive impairment, NIA-AA; National Institute on Aging and the Alzheimer’s Association.