A Skull Bone Marrow-to-Brain Axis Links Osteoblastic Activity to Myeloid Cell Trafficking, Cerebral Blood Flow, and Cognition in Alzheimer's Progression.

Patients with Alzheimer's disease (AD) often develop osteoporosis, but the role of bone remodeling in AD remains unclear. We previously showed that osteoblast-specific expression of APPswe induces bone loss, glial activation, and behavioral deficits, suggesting a bone-to-brain signaling axis. Here, we identify an altered skull bone marrow (SBM)-to-brain axis in AD. Early SBM changes, including reduced cellularity, increased density, and expanded vascular channels to the meninges, occur in multiple APPswe mouse models. These vascular changes facilitate migration of SBM-derived myeloid cells into the meninges and cortex, improving cerebral blood flow (CBF) and slowing cognitive decline. Notably, these effects are age-dependent, emerging at 6 months but diminishing by 12 months. Enhancing this axis via bone marrow transplantation improves CBF and cognitive function in aged mice, whereas disrupting it through osteoblastic deletion of ATP6AP2 impairs both. Together, these findings reveal a previously unrecognized SBM-to-brain axis that regulates immune, vascular, and cognitive functions, highlighting systemic contributions to AD pathogenesis.