Distinct longitudinal brain white matter microstructure changes and associated polygenic risk of common psychiatric disorders and Alzheimer’s disease in the UK Biobank

Background During the course of adulthood and aging, white matter (WM) structure and organization are characterized by slow degradation processes such as demyelination and shrinkage. An acceleration of such aging process has been linked to the development of a range of diseases. Thus, an accurate description of healthy brain maturation, in particular, in terms of WM features, provides a cornerstone in the understanding of aging. Methods We use longitudinal diffusion magnetic resonance imaging to provide an overview of WM changes at different spatial and temporal scales in the UK Biobank (UKB) (N=2,678; agescan 1=62.38±7.23 years; agescan 2=64.81±7.1 years). To examine the genetic overlap between WM structure and common clinical conditions, we tested the associations between WM structure and polygenic risk scores (PGRS) for the most common neurodegenerative disorder, Alzheimer's disease, and common psychiatric disorders (uni- and bipolar depression, anxiety, obsessive-compulsive, autism, schizophrenia, attention-deficit-hyperactivity) in longitudinal (N=2,329) and cross-sectional UKB validation data (N=31,056). Results Our findings indicate spatially distributed WM changes across the brain, as well as distributed associations of PGRS with WM. Importantly, brain longitudinal changes reflected the genetic risk for disorder development better than the utilized cross-sectional measures, with regional differences giving more specific insights into gene-brain change associations than global averages. Conclusions We exctend recent findings by providing a detailed overview of WM microstructure degeneration on different spatial levels, helping to understand fundamental brain ageing processes. Further longitudinal research is warranted to examine ageing-related gene-brain associations.