Border-Associated Macrophage Migrasomes in Alzheimer’s Disease: An Emerging Aβ–Senescence–Microglia Axis?

Alzheimer’s disease (AD) involves not only the neural parenchyma but also brain-border interfaces in which border-associated macrophages (BAMs) regulate amyloid-β (Aβ) handling, vascular function, and immune surveillance. This review focuses on a pathological axis in which persistent vascular Aβ40 and aging-related stress shift clearance-competent BAMs toward oxidative-stress and senescent-like states. Two experimentally supported but incompletely connected branches are emphasized. In one, Aβ engages macrophage CD36–NOX2 signaling and generates reactive oxygen species that impair neurovascular function. In the other, Aβ40 internalization promotes TSPAN4-dependent migrasome formation and enrichment of CD5L/AIM; vascularly deposited CD5L/AIM lowers endothelial CD59, facilitates C5b–9 formation, and damages the blood–brain barrier. A separate aging study indicates that CD5L/AIM-rich BAM migrasomes can transmit apoptosis resistance and senescence-like dysfunction to microglia. Human evidence is currently strongest for CAA rather than parenchymal AD: a small CAA cohort showed increased circulating CD14-positive migrasomes and monocyte TSPAN4, with an exploratory area under the ROC curve of approximately 0.91 for TSPAN4-positive monocytes versus healthy controls, whereas AD patients selected to lack imaging evidence of CAA did not show increased circulating migrasome counts. Accordingly, the Aβ40–TSPAN4–CD5L/AIM vascular branch should presently be regarded as a CAA-enriched mechanism that may be especially relevant to AD with prominent CAA, not as a universal mechanism of Aβ42-dominant sporadic AD without substantial vascular amyloid. Direct demonstration of BAM-derived migrasomes in human AD brain tissue is still lacking, and neither TSPAN4 nor CD5L/AIM is sufficiently specific to serve as a stand-alone biomarker. We therefore distinguish peer-reviewed human observations, experimental causal evidence, preprint findings, and proposed cross-pathway interactions and outline biomarker validation and pathway-selective therapeutic strategies that preserve beneficial BAM functions.