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 (AD), 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 MRI, including phase-contrast and pseudo-continuous arterial spin labeling, was performed in mouse models of amyloidosis (5xFAD), VSMC degeneration (CADASIL), and lipopolysaccharide-induced neuroinflammation. Characterization of vascular, amyloid-β, 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-β 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 AD.

HIGHLIGHTS: Cerebrovascular reactivity (CVR) impairment occurred in 5xFAD mice only when vascular smooth muscle cell (VSMC) loss was present5xFAD mice exhibited prominent parenchymal but minimal vascular amyloid-β depositionVSMC developmental deficiency resulted in CVR impairment in a small-vessel disease (SVD) modelNeuroinflammation primarily altered baseline cerebral blood flow (CBF) without affecting CVR.