Skull Bone Marrow as a Cranial Neuroimmune Reservoir in Alzheimer’s Disease: Amyloid, Osteoimmune Remodeling, and Translational Imaging Evidence

Alzheimer’s disease (AD) has traditionally been conceptualized as a disorder driven primarily by cerebral amyloid-β accumulation, tau pathology, synaptic failure, vascular dysfunction, and chronic neuroinflammation. However, emerging evidence suggests that AD pathobiology may also involve extracerebral cranial compartments positioned at the interface between the brain, meninges, cerebrospinal fluid, and skull bone marrow. Recent anatomical and experimental studies have identified direct vascular and osseous channels connecting skull bone marrow with the dura mater, allowing bidirectional exchange of immune cells, soluble mediators, and cerebrospinal fluid-derived signals. These findings support the concept that skull bone marrow functions as a specialized cranial immune reservoir capable of sensing central nervous system-derived molecular cues and supplying myeloid and lymphoid cells to meningeal and brain-border compartments. In AD models and human imaging studies, amyloid-β-related signals have been detected in skull marrow, where they may promote IL-6-dependent B lymphopoiesis, expansion of age-associated B cells, microglial activation, and amplification of cerebral amyloid pathology. In parallel, AD-related amyloid precursor protein and amyloid-β signaling may remodel the skull marrow niche through osteoblast dysfunction, altered osteoclast activity, vascular channel expansion, marrow adiposity, and inflammatory reprogramming. Human PET and MRI studies indicate that skull marrow-associated inflammatory, amyloid-related, and cerebrospinal-fluid drainage signals can be detected in vivo; however, these observations remain indirect, method-dependent, and insufficiently validated for diagnostic or prognostic use. Importantly, much of the anatomical foundation for skull marrow–meninges–brain communication derives from non-AD studies of CNS-border physiology, stroke, meningitis, spinal cord injury, and infection, whereas the strongest AD-specific mechanistic evidence is currently derived from transgenic mouse models. Accordingly, we frame the skull marrow–meninges–brain axis as a testable conceptual model rather than an established causal pathway in human AD. This review integrates anatomical, immunological, osteoimmune, and imaging evidence while explicitly distinguishing AD-specific findings from evidence extrapolated from other neurological or inflammatory contexts. Determining whether skull marrow alterations represent a cause, consequence, compensatory response, or amplifier of AD pathology will require longitudinal, biomarker-defined human studies and further mechanistic validation. The review also compares the principal in vivo strategies used to distinguish skull-marrow-derived immune cells from circulating leukocytes and examines ischemic stroke and brain tumors as comparator CNS conditions. These disease models demonstrate that cranial marrow responses can be rapid, spatially organized, and either protective or pathogenic depending on cellular phenotype and disease context, reinforcing the interpretation of skull marrow as a general CNS-border immune organ rather than an AD-specific compartment.