The underlying neurobiology of social isolation and loneliness in middle-older adults: A systematic review

Social isolation and loneliness are distinct but overlapping dementia risk factors, though their underlying neurobiological mechanisms remain unclear. A systematic search identified 42 studies examining social isolation, loneliness, and neurobiological outcomes in middle-aged and older adults, including structural and functional neuroimaging, neuroinflammatory, and neurodegenerative markers. Findings identified patterns of neurobiological associations that were reported exclusively for social isolation, exclusively for loneliness, and shared across both concepts. Social isolation was more frequently associated with temporal regions (middle temporal gyrus, temporal lobe), whereas loneliness demonstrated associations with subcortical structures (putamen, globus pallidus). Shared patterns of association were most evident in limbic regions (hippocampus, amygdala, thalamus, fusiform gyrus). Both constructs were also associated with greater white matter hyperintensity/lesion volume and elevated C-reactive protein. Several implicated regions are vulnerable in dementia, suggesting potential neurobiological pathways linking poor social health to neurodegenerative risk. However, substantial methodological heterogeneity and inconsistent measurement approaches limit conclusions and highlight important directions for future research.