This study aimed to investigate the associations between social isolation, loneliness, and brain health including both neurological and psychiatric disorders, as well as various behavioral phenotypes.

Social isolation and loneliness present significant health risks, especially for cardiovascular disease, diabetes, and earlier mortality. However, their effects on brain health remain inadequately understood.

In the UK Biobank (UKB; N=383,421), we used Cox models to assess incident risk for 13 neurological/psychiatric disorders and Mendelian randomization (MR) to test causality. Linear regression was applied to UKB and the Chinese Alzheimer’s Biomarker and LifestyLE (CABLE) study (N=967) to associate social isolation and loneliness with cognitive/emotional functions and neurobiological markers (UKB brain structure; CABLE CSF Alzheimer's disease (AD) biomarkers). Finally, we examined the mediating role of blood inflammatory/biochemical markers in the relationships with brain disorder risk.

Firstly, we identified significant associations between social isolation, loneliness, and the incidence of 7 neurological disorders, including dementia, AD, Parkinson's disease, stroke, multiple sclerosis, epilepsy, and sleep disorders, and 4 psychiatric disorders including schizophrenia, bipolar affective disorder, anxiety disorders, and major depressive disorder (MDD). MR analyses confirmed the relationship from loneliness to sleep disorders, schizophrenia, and MDD. Secondly, we observed significant cross-sectional associations of social isolation, loneliness and behavioral phenotypes, including worse cognition, emotion and movement, and altered brain structures, including cortical (lingual, lateral occipital, and inferior parietal cortex) and subcortical (nucleus accumbens, hippocampus, thalamus, lateral ventricle) regions, as well as white matter hyperintensities, and CSF AD pathological biomarkers, including decreased CSF Aβ42 and Aβ40 levels, and increased CSF T-tau/Aβ42 ratio. Additionally, the mediation analysis indicated that the peripheral inflammatory and biochemical markers might partially mediate the associations of social isolation, loneliness and neuropsychiatric disorders.

Thus, addressing social isolation and loneliness is imperative for the prevention of brain disorders, especially dementia and psychiatric disorders.