Multimodal in Vivo Biomarker-Based Investigation of Alzheimer’s Disease Pathophysiology and Drug Discovery

• Main Author: Kang, Min Su
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2021
• Subjects: Aging; Alzheimers disease; Biomarkers; Gerontology; Magnetic resonance imaging; Medical imaging; Medicine; Neurodegeneration; Neurosciences; Pathology
• ISBN: 9798841573746

in vivo biomarkers of Alzheimer’s disease (AD) have made remarkable progress during the past decades in detecting the pathological hallmarks of AD: aggregates of amyloid-beta (Aβ) plaques, aggregates of hyperphosphorylated tau/neurofibrillary tangles (NFTs), and neurodegeneration. Today, such biomarkers can be quantified using advanced brain imaging techniques such as positron emission tomography (PET) as well as more readily available and accessible biofluid platforms such as in cerebrospinal fluid (CSF) and/or plasma sampling. In 2018, the US National Institute of Aging (NIA) and Alzheimer’s Association (AA) has put forth a research framework, the A/T/(N) classification system – Aβ, hyperphosphorylated tau, and neurodegeneration, in which the diagnostic criteria are now exclusively based on the biological construct of AD. Although the application of the biological-based diagnostic criteria on clinical diagnosis of AD is still debated, the A/T/(N) system has provided a consensus in the AD research community. This has 1) accelerated the discoveries and validations of novel biomarkers across a multitude of platforms, 2) promoted a deeper understanding and a more accurate characterization of AD pathophysiological processes leading to cognitive impairment, 3) enabled clinical trial enrichment by precisely defining the potential therapeutic target, intervention study design, and biomarker-based evaluation of therapeutic target engagement and efficacy.In this Ph.D. thesis, three original studies provide three novel findings using the A/T/(N) classification research framework to 1) validate a novel fluid neuronal injury biomarker, neurofilament light chain (NFL) as a new addition to the AD biomarker A/T/(N) classification, 2) support activated microglia as an important factor in AD pathophysiological processes leading to aggregation of hyperphosphorylated tau and subsequent cognitive impairment in the presence of Aβ, and 3) demonstrate a potential disease-modifying AD therapeutic and a platform, in which to facilitate new drug discovery