An MRI‐based macro‐ and microstructural neuroimaging‐wide association study of subsequent cognitive impairment

INTRODUCTION This study longitudinally examined 154 magnetic resonance imaging (MRI) biomarkers in cognitively normal (CN) individuals to identify structural brain changes most strongly associated with subsequent cognitive impairment (SI). METHODS We analyzed 509 Baltimore Longitudinal Study of Aging participants (age ≥ 50, CN at baseline) with longitudinal cognitive and 3T MRI (T1/T2‐weighted scans and diffusion tensor imaging) data. MRI biomarker associations with SI status were analyzed, adjusting for confounders and stratifying by sex and amyloid beta (Aβ) status. RESULTS Participants who developed SI over 4.6 years’ follow‐up showed greater longitudinal changes in white matter (WM) integrity, particularly in the corpus callosum, cingulum bundle, and inferior fronto‐occipital fasciculus, compared to CN‐stable. To a lesser degree, we also observed temporal thinning and atrophy linked to SI. These associations were amplified among males and amyloid‐positive individuals. DISCUSSION Longitudinal alterations in WM microstructural integrity were most strongly associated with future impairment, highlighting the importance of early WM changes in the development of MCI and dementia.