Vascular cognitive decline may be caused by micro-emboli generated by carotid plaque instability. We previously found that maximum strain indices in carotid plaque were significantly correlated with cognitive function. In the work described here, we examined these associations with a larger sample size, as well as evaluated the performance of these maximum strain indices in predicting cognitive impairment. Ultrasound-based strain imaging and cognition assessment were conducted on 75 human patients. Patients underwent one of two standardized cognitive test batteries, either the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) or the National Institute of Neurologic Disorder and Stroke-Canadian Stroke Network (NINDS-CSN) Vascular Cognitive Impairment Harmonization Standards (60 min). Scores were standardized within each battery to allow these data to be combined across all participants. Radiofrequency signals for ultrasound strain imaging were acquired on the carotid arteries using either a Siemens Antares with a VFX 13-5 linear array transducer or a Siemens S2000 with an 18 L6 linear array transducer. The same hierarchical block-matching motion tracking algorithm developed in our laboratory was used to estimate accumulated axial, lateral, and shear strain indices in carotid plaque, with inclusion of adventitia regardless of the ultrasound system and transducer used. Associations between cognitive z-scores and maximum strain indices were examined using Pearson's correlation coefficients. Maximum strain indices were also employed to predict cognitive impairment using receiver operating characteristic analysis. All correlations between maximum strain indices and total cognition were statistically significant (p < 0.05), indicating that these indices have good utility in predicting cognitive impairment. Maximum lateral strain indices provided an area under the curve of 0.85 for symptomatic patients and 0.68 for asymptomatic patients. Our results indicate the important relationship of maximum strain indices to cognitive function and the feasibility of using maximum strain indices to predict cognitive decline with inclusion of the adventitia layer into the segmentation of plaque.