Vascular smooth muscle cell loss, but not neuroinflammation, drives cerebrovascular reactivity impairment in Alzheimer's disease.

INTRODUCTION

Cerebrovascular reactivity (CVR) impairment is a key feature of Alzheimer's disease and related dementias (ADRD), but its mechanistic basis remains unclear. This study examined whether vascular smooth muscle cell (VSMC) loss, rather than amyloidosis or neuroinflammation, underlies CVR deficits.

METHODS

Non-contrast magnetic resonance imaging (MRI), including phase-contrast and pseudo-continuous arterial spin labeling, was performed in mouse models of amyloidosis (five familial Alzheimer's disease mutations [5xFAD]), VSMC degeneration (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]), and lipopolysaccharide-induced neuroinflammation. Characterizations of vascular, amyloid beta, and inflammatory markers were performed for pathological assessment.

RESULTS

CVR impairment emerged only when VSMC loss was present in CADASIL mice and at older ages in 5xFAD mice (9-12 months). Amyloid beta deposition occurred earlier than VSMC loss or CVR decline. Neuroinflammation primarily altered baseline cerebral blood flow without affecting CVR or VSMC integrity.

DISCUSSION: These findings identify VSMC degeneration as an important driver of CVR impairment independent of cerebral amyloid angiopathy or inflammation, highlighting vascular integrity as a potential therapeutic target in ADRD.