UC San Diego

Alzheimer’s disease is a debilitating, slowly progressive neurodegenerative disorder affecting over 50 million people globally, a figure expected to increase to 152 million by 2050. Not only is there a long prodromal period wherein individuals show early signs and risk factors for the disease, which are often mistaken as effects of normal aging, but insidious pathological processes are thought to begin taking place in the brain decades before individuals show severe cognitive impairments. Suitably, recent research efforts have focused on detecting signs of ad earlier in life to identify the disease preclinically and before irreversible damage occurs. However, knowing what to focus on in this preclinical period is proving to be a considerable challenge. The locus coeruleus (LC) is a small brainstem nucleus critical for healthy brain functioning that has been implicated in the pathogenesis of Alzheimer’s, and recent advances in neuroimaging allow for in-vivo examination. This dissertation aims to characterize the LC in-vivo using magnetic resonance imaging (MRI), neuropsychological testing, and biomarker assessment, with the goal of bettering our understanding of prodromal AD and AD risk. In Chapter 1 I detail our work optimizing a novel diffusion MRI analysis tool to establish a reliable method for reconstructing an LC projection pathway to the transentorhinal cortex, a region heavily affected by AD pathology. In Chapter 2, I explore how equilibrium probability within this pathway relates to cognition in the context of tau and amyloid biomarkers. Finally, in Chapter 3 I use an LC-sensitive anatomical MRI scan to measure relative LC signal, potentially a marker of nuclear integrity, and examine its associations with cognition in the context of tau and amyloid. Importantly, I show that the relationship between these MRI markers and cognition depends on tau and amyloid status, implicating a more complex relationship between macroscopic imaging measures and cognitive outcomes. This work has implications for preclinical AD research as well as clinical neuroimaging research aiming to uncover in-vivo disease markers in general.