Abstract BACKGROUND Peak‐width of skeletonized mean diffusivity (PSMD), a neuroimaging marker of cerebral small vessel disease (SVD), has shown excellent instrumental properties. Here, we extend our work to perform a biological validation of PSMD. METHODS We included 396 participants from the Biomarkers for Vascular Contributions to Cognitive Impairment and Dementia (MarkVCID‐1) Consortium and three replication samples (Cohorts for Heart and Aging Research in Genomic Epidemiology = 6172, Rush University Medical Center = 287, University of California Davis Alzheimer's Disease Research Center = 567). PSMD was derived from diffusion tensor imaging using an automated algorithm. We related PSMD to a composite measure of general cognitive function using linear regression models adjusting for confounders. RESULTS Higher PSMD was associated with lower general cognition in MarkVCID‐1 independent of age, sex, education, and intracranial volume (Beta [95% confidence interval], −0.8 [−1.2, −0.4], P &lt; 0.001). These findings were replicated in independent samples. Furthermore, PSMD explained cognitive status above and beyond white matter hyperintensities. DISCUSSION Our biological validation work supports the pursuit of larger clinical validation studies evaluating PSMD as a susceptibility/risk biomarker of small vessel disease contributing to cognitive impairment and dementia. Highlights Peak‐width of skeletonized mean diffusivity (PSMD) is a novel small vessel disease neuroimaging biomarker. A prior instrumental validation study demonstrated that PSMD is a robust biomarker. This biological validation study shows that high PSMD relates to worse cognition. PSMD explains cognitive function above and beyond white matter hyperintensities. Future clinical validation will assess PSMD as a vascular contribution to cognitive impairment and dementia biomarker in clinical trials.

Biological validation of peak‐width of skeletonized mean diffusivity as a VCID biomarker: The MarkVCID Consortium