Characterizing vascular function in mouse models of Alzheimer's disease, atherosclerosis, and mixed Alzheimer's and atherosclerosis.

Significance: Alzheimer's disease does not occur in isolation, and there are many comorbidities associated with the disease, especially diseases of the vasculature. Atherosclerosis is a known risk factor for the subsequent development of Alzheimer's disease; therefore, understanding how both diseases interact will provide a greater understanding of co-morbid disease progression and aid the development of potential new treatments. Aim: We characterize hemodynamic responses and cognitive performance in APP/PS1 Alzheimer's mice, atherosclerosis mice, and a mixed disease group (APP/PS1 and atherosclerosis) between the ages of 9 and 12 months. Approach: Whisker-evoked hemodynamic responses and recognition memory were assessed in awake mice, immunohistochemistry to assess amyloid pathology, and histology to characterize atherosclerotic plaque load. Results: We observed hemodynamic deficits in atherosclerosis mice (versus Alzheimer's, mixed disease, or wild-type mice), with reduced short-duration stimulus-evoked hemodynamic responses occurring when there was no concurrent locomotion during the stimulation period. Mixed Alzheimer's and atherosclerosis models did not show differences in amyloid beta coverage in the cortex or hippocampus or atherosclerotic plaque burden in the aortic arch vs relevant Alzheimer's or atherosclerosis controls. Consistent with the subtle vascular deficits and no pathology differences, we also observed no difference in performance on the object recognition task across groups. Conclusions: These results emphasize the importance of experimental design for characterizing vascular function across disease groups, as locomotion and stimulus duration impacted the ability to detect differences between groups. Although atherosclerosis did reduce hemodynamic responses, these were recovered in the presence of co-occurring Alzheimer's disease, which may provide targets for future studies to explore the potentially contrasting vasodilatory mechanisms these diseases impact.