Plasma biomarkers of neurodegeneration across the spectrum of brain health

Over the past decade, remarkable progress has been made in the development of plasma biomarkers for neurodegenerative diseases, particularly for diagnosis of Alzheimer’s Disease (AD). These biomarkers have considerable potential to transform clinical practice by providing accessible, cost-effective, and minimally invasive tools for early detection, and diagnosis of AD. However, despite rapid international progress, significant gaps remain before these biomarkers can be fully implemented in clinical care within Canada. This thesis addresses several of these gaps through analysis of plasma amyloid beta (Aβ42/40), phosphorylated tau-181 (p-tau-181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) across four cohorts representing the spectrum of brain health. Using a large normative population representing Canadians across the lifespan, we address the need for a deeper understanding of how biomarker concentrations vary across normal aging through the establishment of age-specific reference intervals. Here, we found that between the ages of 3-79 years old, all biomarkers exhibited U-shaped curves as a function of age. Next, we explore biomarker signatures in individuals with cognitive resilience, providing insight into biomarker response among individuals who remain cognitively intact despite advanced age. This analysis revealed potentially resilient levels of Aβ42/40 and p-tau-181, but levels of NfL and GFAP that were reflective of the normative population. Subsequent chapters link plasma biomarker profiles to autopsy-confirmed neuropathology, addressing a critical knowledge gap in understanding the pathological specificity of these measures for AD compared with other dementias. Here, we were able to identify the domains of AD neuropathology that plasma biomarkers best inform on. Finally, by leveraging a multi-cohort design, this thesis identifies and validates diagnostic cut-offs for AD pathology. This work provides evidence for biomarker application in real-world settings, and assesses concordance between pathology and clinical diagnoses across disease stages. Collectively, the studies presented in this thesis contribute foundational data to guide the clinical translation of neurodegenerative blood biomarkers in Canada, enabling their eventual adoption into diagnostic workflows for dementia.