Impact of Insulin Resistance and Metabolic Status on Brain and Cognitive Aging

Abstract

The aging process brings forth profound challenges, particularly in safeguarding cognitive health and mitigating the risk of neurodegenerative diseases such as Alzheimer's disease (AD). This doctoral thesis explores the role of peripheral insulin resistance (IR) and related cardiometabolic factors in shaping brain structure, functional organization, and cognitive performance in cognitively normal older adults. Structured around three cross-sectional studies, this work seeks to unravel the mechanisms underpinning variability in cognitive and neural aging by integrating advanced neuroimaging techniques, comprehensive neuropsychological assessments, and detailed cardiometabolic profiling. Study 1 investigated the neuroprotective role of the adiponectin-leptin (Ad/L) ratio, revealing that higher values were linked to better cognitive performance and preserved cortical thickness in key prefrontal regions. The findings highlighted the role of early metabolic compensation, where brain health is still preserved even in the presence of elevated IR, while glucose levels remain normal. This study underscores how the Ad/L ratio can safeguard age-related cortical atrophy by maintaining a favorable metabolic balance. Study 2 examined whether elevated fasting glucose levels alter the functional organization of default-mode network hubs in cognitively normal older adults. Elevated glucose was linked to poorer metabolic health, and sex-specific patterns emerged: women with higher IR showed increased long-range functional connectivity in the right precuneus, possibly compensating for early glycemic dysfunction, while men exhibited reduced short-range functional connectivity in the left medial orbitofrontal cortex, a critical energy-efficient hub. These shifts in brain's functional organization, though potentially protective initially, expose underlying metabolic vulnerabilities and highlight early network disruptions that may precede cognitive decline and AD risk. Study 3 focused on spatial navigation abilities, with a particular emphasis on path integration (PI), as a marker of cognitive resilience during navigation. The interplay between IR, APOE €4 genotype, and cortical integrity was explored, showing distinct patterns of functional network reorganization. Unexpectedly, APOE €4 carriers benefited from explicit spatial cues, displaying enhanced PI performance, but showed greater vulnerability when such cues were absent. Their PI outcomes were further moderated by cortical gray matter integrity, indicating that structural brain characteristics influence how APOE €4 affects navigation. In contrast, IR did not directly impair PI; instead, its impact emerged through altered functional network segregation. Different IR levels prompted shifts between reliance on specialized or integrated networks to maintain PI, without gray matter moderation. These findings suggest separate structural and functional mechanisms by which APOE €4 and IR shape spatial navigation strategies. Together, these studies shed light on the complex interactions between metabolic health, APOE €4 genotype, and brain function, offering novel insights into the mechanisms that shape cognitive variability during aging. By identifying key markers of vulnerability and resilience, this thesis provides a foundation for targeted interventions focused on metabolic factors to preserve brain health and mitigate cognitive decline.