Cerebral Intramural Cells: A Missing Cellular Link Between Vascular Aging and Alzheimer's Disease

The pathological deposition of amyloid-β (Aβ) in the walls of cerebral blood vessels as cerebral amyloid angiopathy (CAA) is a key feature of Alzheimer's disease (AD) and is linked to impaired clearance of Aβ via intramural periarterial drainage (IPAD). The spontaneous contractions of cerebral smooth muscle cells (SMCs) are thought to drive IPAD, but the relationship between vascular aging and Aβ accumulation remains unclear. We propose a unified framework centered on cerebral intramural cells (CICs), including arterial SMCs, specialized pericyte subtypes, as mediators of vascular dysfunction and neurodegeneration. We integrate current evidence from studies of cerebral small vessel disease, blood-brain barrier (BBB) dysfunction, pericyte biology, vascular aging, cerebral perfusion, and IPAD. CICs regulate vasomotion, capillary flow, BBB integrity, and IPAD. Their dysfunction impairs perfusion and protein clearance, increasing vulnerability in white matter and the hippocampus. These vascular alterations interact with amyloid and inflammatory processes, contributing to synaptic dysfunction, network disconnection, and neurodegeneration. CICs represent potential therapeutic targets. A CIC-centered framework may help explain the links between vascular dysfunction, impaired Aβ clearance, and neurodegeneration in AD and CAA.