Background:Social isolation has been suggested to increase the risk to develop cognitive decline. However, our knowledge on causality and neurobiological underpinnings is still limited.Methods:In this preregistered analysis, we tested the impact of social isolation on central features of brain and cognitive ageing using a longitudinal population-based magnetic resonance imaging (MRI) study. We assayed 1992 cognitively healthy participants (50–82years old, 921women) at baseline and 1409 participants after~6y follow-up.Results:We found baseline social isolation and change in social isolation to be associated with smaller volumes of the hippocampus and clusters of reduced cortical thickness. Furthermore, poorer cognitive functions (memory, processing speed, executive functions) were linked to greater social isolation, too.Conclusions:Combining advanced neuroimaging outcomes with prevalent lifestyle characteristics from a well-characterized population of middle- to older aged adults, we provide evidence that social isolation contributes to human brain atrophy and cognitive decline. Within-subject effects of social isolation were similar to between-subject effects, indicating an opportunity to reduce dementia risk by promoting social networks.Funding:European Union, European Regional Development Fund, Free State of Saxony, LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, German Research Foundation.