Associations of white matter microstructural damage with both cross-sectional and longitudinal cognitive decline in cerebral amyloid angiopathy and non-CAA mild cognitive impairment

Background Peak width of skeletonized mean diffusivity (PSMD) is an automated diffusion marker that captures white matter microstructural damage more sensitively than conventional small vessel disease markers. We investigated the cross sectional and longitudinal associations of PSMD and amyloid β (A β ) burden with cognition, and whether concomitant cerebral amyloid angiopathy (CAA) modifies these relationships in mild cognitive impairment (MCI). Methods A total of 124 MCI patients were included from the Alzheimer’s Disease Neuroimaging Initiative, classified as CAA-MCI or non-CAA MCI by Boston criteria version 2.0. Cross-sectional and longitudinal associations between baseline PSMD, amyloid burden, and cognitive outcomes were assessed using linear regression, linear mixed-effects models, and Cox proportional hazards models. Results PSMD showed strong cross-sectional associations with processing speed and executive function, however this association was not modified by CAA status. No significant difference for longitudinal cognition changes between CAA and non-CAA groups. Within CAA-MCI, higher PSMD correlated with lower A β burden but not with cognition. Over 4 years, PSMD did not predict decline after correction for multiple comparisons in both CAA and non-CAA groups. Greater A β burden predicted multi- domain decline and dementia conversion in both groups, and the A β -associated decline in global cognition was steeper in CAA-MCI. Conclusion PSMD indexed current processing speed and executive function rather than subsequent change, independently of conventional small vessel disease markers and of CAA, whereas A β burden drove longitudinal decline and dementia conversion. The two biomarkers therefore appear to capture processes unfolding on different time scales. Whether concomitant CAA modifies amyloid-related decline requires confirmation in larger cohorts.