BackgroundSocial isolation is a risk factor for dementia, a devastating disease with a rapidly growing global prevalence. However, the link between social isolation and changes in brain structure and function is poorly understood, as studies are scarce in number, methodologically inconsistent and small in size. In this pre-registered analysis of a large population-based panel study, we aimed to determine the impact of social isolation on brain structures and cognitive functions central to age associated decline and dementia.Methods and findingsWe analysed data of 1992 cognitively healthy participants of the LIFE-Adult study at baseline (age range: 50-82 years) and of 1409 particpants at follow-up (average change in age: 5.89 years). We measured social isolation using the 30-point Lubben Social Network Scale (LSNS) and derived measures of grey matter structure from anatomical 3T MRIs. We employed covariate adjusted linear mixed models to test the associations of baseline social isolation and change in social isolation with hippocampal volume, cognitive functions (executive functions, memory, processing speed) and cortical thickness.We found stronger baseline social isolation to be significantly associated with smaller hippocampal volumes (β = −5.5 mm3/LSNS point(pt), FDR q = 0.004, BF = 14.6) and lower cognitive functions (all β < −0.014 SD/pt, FDR q < 0.003, BF > 49). Increases in social isolation over time were linked to hippocampal volume decline (β = −4.9 mm3/pt, FDR q = 0.01, BF = 2.9) and worse memory performance (β = −0.013 SD/pt, FDR q = 0.04, BF = 1.1). Furthermore, we detected a significant interaction of baseline social isolation with change in age on hippocampal volume (β = −0.556 mm3/pt*a, q = 0.04, BF = 0.5), indicating accelerated brain aging in more isolated individuals. Moreover, social isolation cross-sectionally and longitudinally correlated with lower cortical thickness in multiple clusters in the orbitofrontal cortex, precuneus and other areas (FDR q < 0.05).ConclusionsHere, we provide evidence that social isolation contributes to hippocampal and cortical atrophy and subtle cognitive decline in non-demented mid-to late-life adults. Importantly, within-subject effects of social isolation were similar to between-subject effects, indicating an opportunity for targeting social isolation to reduce dementia risk.