Intermittent hypoxia training alleviates cerebral hypoperfusion and amyloid-β deposition in a mixed dementia model established by bilateral common carotid artery stenosis in early-stage 5xFAD mice

Background Alzheimer's disease (AD) is the most common form of dementia and often coexists with vascular pathology in clinical settings, resulting in mixed dementia with more severe symptoms and more rapid progression. Objective To investigate whether chronic cerebral hypoperfusion aggravates early AD-related pathology, we established a mixed dementia-like model by inducing bilateral common carotid artery stenosis (BCAS) in early-stage 5xFAD mice and evaluated the effects of intermittent hypoxia treatment (IHT). Methods Early-stage 5xFAD mice were subjected to BCAS to induce chronic cerebral hypoperfusion. Cognitive performance, cerebral perfusion, amyloid-β (Aβ) deposition, glial reactivity, tight-junction transcripts, and perivascular astrocyte–vascular organization were assessed. The therapeutic effects of IHT were then evaluated in this mixed dementia-like model. Results BCAS-induced hypoperfusion aggravated cognitive impairment in early-stage 5xFAD mice and accelerated pathological changes, including increased Aβ burden and stronger glial reactivity. These changes were accompanied by altered tight-junction transcripts and impaired perivascular astrocyte–vascular organization. IHT mitigated several features of the mixed dementia phenotype, including cerebral hypoperfusion, Aβ accumulation, glial reactivity, and altered perivascular AQP4/CD31 organization, while partially improving cognitive performance. Conclusions Chronic cerebral hypoperfusion can exacerbate early AD-related pathological and cognitive changes. IHT may alleviate mixed dementia-like phenotypes by improving cerebral perfusion, with accompanying changes in perivascular AQP4/CD31 organization and tight-junction transcripts.