Linking Brain Networks and Gut Microbiota to Cognitive Impairment and Depressive Symptoms in Late Life

Major neurocognitive disorder (MNCD) or dementia is a widespread condition affecting more than 50 million individuals, resulting in memory loss and communication difficulties. Late life depression (LLD) occurring alongside MNCD exacerbates the symptoms and imposes a substantial burden on society and healthcare. Finding effective treatments for MNCD and LLD is crucial, but options are currently limited. The search for neurobiologically informed treatment targets involves many efforts, including quantitatively mapping clinical symptoms onto neural networks, as well as exploring the therapeutic potential of manipulating the gut-brain axis. Despite emerging research on midlife depression and cognition in the context of the gut-brain axis, our understanding of the microbiota-gut-brain relationship in individuals with mild cognitive impairment (MCI) or MNCD, especially when accompanied by varying degrees of depressive symptoms, remains considerably limited. This dissertation aims to unravel the complex interplay between gut microbiota, brain function, cognitive capacities, and depressive symptoms within the specific framework of MCI or MNCD, both with and without comorbid LLD. Chapter 2 (Aim 1) of the dissertation examines the links between gut microbiome diversity, cognitive function, and depressive symptoms. It explores the connection between the richness and evenness of the gut microbiota (alpha diversity) and cognitive function or depressive symptoms. Additionally, it explores whether depressive symptoms and cognitive function interact to influence alpha diversity. iv Chapters 3 and 4 (Aim 2) delve into the relationships between brain functional connectivity, cognitive function, depressive symptoms, and alpha diversity. Chapter 3 investigates which resting state features are most strongly associated with cognitive function or depressive symptoms. Chapter 4 explores whether the relationship between alpha diversity, cognitive function, or depressive symptoms is partially mediated by specific functional connectivity features. In conclusion, this dissertation presents a thorough exploration of the microbiota-gut-brain axis and its implications for cognitive function and depressive symptoms in older adults. The findings have the potential to provide valuable insights and innovative interventions for individuals dealing with these conditions, ultimately reducing the societal burden of MNCD and related disorders.