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. In vivo two-photon microscopy was used to longitudinally measure cerebral amyloid angiopathy vessel coverage and amyloid-β tissue plaque volume. We observed that APP/PS1 mice exhibited attenuated neurovascular coupling during whisker stimulation and this response worsened through lifespan compared to controls. Compared to controls, APP/PS1 mice exhibited decreased carbon dioxide reactivity with age. No sex differences between control mice were observed in the neurovascular response to whisker, whereas during hypercapnia, control females had higher carbon dioxide reactivity than control males. While both APP/PS1 males and females showed reduced dilatory responses with age, APP/PS1 females exhibited this decrease in small arteries, whereas APP/PS1 males experienced decreased dilation in larger arteries. Diminished vascular reactivity in APP/PS1 mice was associated with increased cerebral amyloid angiopathy and amyloid-plaque burden. This study highlights sex-specific pathophysiology's of vascular dysfunction across the lifespan. Our findings underscore needs to incorporate sex differences in preclinical Alzheimer's disease research, given the rising importance of vascular contributions to cognitive impairment and dementia. Our findings have important implications for developing targeted, age and sex-specific biomarkers and therapeutics for cerebrovascular health in Alzheimer's disease.