Near-lifespan mesoscopic optical imaging of cerebrovascular function reveals age and sex differences in preclinical Alzheimer's disease model.

Growing evidence suggests vascular dysfunction plays a critical role in the early stages of Alzheimer's disease, commonly associated with amyloid-β deposition. This vascular dysfunction is particularly relevant in the context of cerebral amyloid angiopathy, where amyloid-β accumulates within cerebral vessel walls. Notably, sex differences impact progression of both Alzheimer's disease and cerebrovascular dysfunction, with post-menopausal females displaying increased small vessel disease burden and diminished carbon dioxide reactivity compared to older males and pre-menopausal females. Moreover, the cerebrovasculature is a target of sex hormones where they exert influence in numerous vascular functions and pathologies across lifespan. Combined, cerebrovascular dysfunction along with amyloid-β deposition may have differential effects on sex. Despite observational studies in humans, preclinical mechanistic and functional research on sex-specific vascular differences in Alzheimer's disease has been limited. In this near-lifespan longitudinal study, we investigated age and sex-specific neurovascular coupling and carbon dioxide reactivity in a transgenic mouse model expressing chimeric mouse/human amyloid precursor and mutant human presenilin 1 (APP/PS1) and control mice using widefield optical imaging. Neurovascular coupling was probed via whisker stimulation and then vascular reactivity was measured using hypercapnic challenge. During whisker stimulation, neuronal activity was measured through GCaMP6f fluorescence change, while vascular response was quantified via haemoglobin-based optical intrinsic signal. Carbon dioxide reactivity was evaluated by measuring dilatory changes of vessel diameters across the cerebrovascular tree.