Mechanistic link of obesity to depression and cognitive decline in Alzheimer’s disease

The global rise in obesity and metabolic dysfunction has heightened concern about their links to depression, cognitive impairment, and Alzheimer's disease (AD)-related pathology. High-fat diet (HFD) exposure, excess adiposity, and metabolic dysfunction may each contribute to these outcomes, but they represent biologically distinct conditions that should not be treated as interchangeable. Epidemiological evidence suggests links between these conditions, yet the molecular pathways connecting them remain poorly characterized. This systematic review synthesizes current evidence on how HFD exposure, excess adiposity, and metabolic dysfunction may engage overlapping mechanisms associated with depression-related outcomes, cognitive impairment, and AD-related pathology. We propose an integrated biomechanistic model illustrating how HFD exposure may contribute to depression-related outcomes, cognitive impairment, and AD-related pathology through partially overlapping mechanisms. It is presented as a molecular formulation of the classical stress-diathesis perspective, highlighting how dietary exposures may interact with preexisting vulnerabilities, including genetic, epigenetic, and environmental factors, to compromise the brain's adaptive capacity to various stressors. Finally, we discuss translational implications, identifying potential targets for interventions-dietary, pharmacological, and lifestyle-with relevance to shared mechanisms underlying depression-related and cognitive outcomes, while highlighting critical gaps in understanding-such as sex-specific effects, developmental timing, and human translational evidence-that warrant further research. Human evidence remains largely observational and does not establish that these mechanisms operate equivalently in clinically diagnosed depression or AD. Future longitudinal studies integrating dietary exposure, metabolic and inflammatory biomarkers, neuroimaging, cognitive assessment, and clinical diagnoses are needed to define human vulnerability better and to provide targeted prevention and intervention strategies.