Under homeostasis, microglia are separated from monocyte-derived macrophages through the blood-brain barrier, but neuroinflammation can allow monocyte infiltration into the CNS.158 Elevated circulation high-mobility group box 1 (HMGB1), a DAMP capable of inducing trained immunity, is a biomarker for Alzheimer’s disease associated neuroinflammation and blood-brain barrier dysfunction.159,160 Protein aggregates associated with Alzheimer’s and Parkinson’s disease are also recognized as DAMPs through multiple PRRs. Here, HMGB1 is linked to early-onset autosomal dominant Alzheimer disease.