Distinct longitudinal brain white matter microstructure changes and associated polygenic psychiatric and neurodegenerative disorder risk

Motivation: White matter microstructural (WMM) changes are a crucial feature of ageing and disease development. There is yet no comprehensive mapping of such changes. Goal(s): Providing an overview of WMM changes at different spatial scales, and relationship of these changes to polygenic risk scores (PGRS) of developing psychiatric disorders and Alzheimer's disease. Approach: WMM metrics were estimated using multiple diffusion approaches, associated with age and PGRS, and ageing changes (inter-scan interval:2.44±0.73 years) assessed at different spatial scales. Results: We find spatially distributed WMM-changes and PGRS-associations across the brain (most age-sensitive: central and cerebellar WMM). Brain longitudinal changes reflected disorder PGRS better than cross-sectional measures. Impact: The manuscript details for the first time longitudinal WMM changes in a large longitudinal sample (UK Biobank, N=2,676), and provides the currently most comprehensive overview of PGRS associations with WMM change and WMM (using an additional cross-sectional validation sample, N=31,056).