Alzheimer's disease‐associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain

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INTRODUCTION: While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC). METHODS: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association. RESULTS: CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti-HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV-infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau-212) and neuronal death. DISCUSSION: Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+) microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+) microglia. HIGHLIGHTS: Cross-tissue interaction between HCMV and the adaptive immune response in a subset of persons with AD. Presence of CD83(+) microglial associated with IgG4 and HCMV in the gut. CD83(+) microglia are also associated presence of HCMV and IgG4 in the cortex and vagal nerve. Replication of key association in an independent cohort of AD subjects. HCMV infection of cerebral organoids accelerates the production of AD neuropathological features.

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