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Introduction: Cerebral microvascular disease and Alzheimer’s disease (AD) account for the majority of dementia diagnoses with 50% of patients having mixed dementia with features of both microvascular stroke in the white matter and AD pathology. This significant co-morbidity indicates an interactive neurobiologic relationship yet it is unclear if these two pathologies synergize or simply co-exist.Methods: To determine the synergistic effect of subcortical stroke on amyloid deposition, focal subcortical white matter ischemic lesion underneath left sensorimotor cortex or sham procedures were introduced at 2 months of age into E4FAD transgenic mice that express the human ApoE4 knock-in allele together with the 5xFAD transgene or littermate controls. Animals underwent behavioral assessment, brain metabolism analysis by PET/CT, and histologic tissue analysis.Results: In E4FAD-positive mice, subcortical stroke vs. sham resulted in a greater inter-hemispheric difference in amyloid burden in the ipsilateral hemisphere (-0.291 vs. -0.078, p=0.08). This was associated with improved motor recovery on rotarod testing in the E4FAD-positive plus stroke group compared to E4FAD-negative stroke group (53.8 sec vs. 45.23 sec, p=0.016). In E4FAD-positive mice, subcortical stroke vs. sham also resulted in improved hippocampal memory function on fear conditioning (17.6+/-5.0 vs. 32.9+/-5.0, p=0.082) while hippocampal plaque number was not significantly different in this cohort. 18F-FDG PET/CT imaging demonstrated reduced frontal cortex metabolism in the mixed dementia cohort.Conclusions: This novel mouse model of mixed subcortical stroke and Alzheimer’s disease in E4FAD mice illustrates the value of studying the overlap between vascular and Alzheimer’s pathology in the biology of these two common disorders. The combined pathologies demonstrate a potentially paradoxical enhancement in motor recovery and memory impairment compared to stroke or Alzheimer’s disease alone, suggesting that activation of unique molecular pathways in each pathology may partially temper the natural course of each disorder.