Region-of-interest (ROI) metrics are typically computed as a mean over ROI voxels. However, for some NODDI metrics, this approach produces biased estimates in the presence of cerebrospinal fluid partial volume. We address this by introducing a tissue-weighted alternative. We compare the proposed mean to its conventional counterpart for periventricular and non-periventricular ROIs in healthy subjects and patients with young onset Alzheimer’s disease (YOAD). Results show the conventional mean overestimates orientation dispersion index and inflates inter-subject variation, particularly for periventricular ROIs and the YOAD cohort. This technique may improve detection of true regional effects in future group studies of neurodegenerative diseases.