Cytomegalovirus as a Contributing Cause of Some Alzheimer's Disease
There is the suspicion that Alzheimer's disease, like Parkinson's disease, is in fact two or more distinct conditions with quite different root causes that converge on a similar outcome. Whenever there is a struggle to produce good correlations, with competing studies showing different results, it is plausible that the conflicting data arises because different subtypes of the condition are more or less prevalent in one study versus another. Here, researchers propose that one subtype of Alzheimer's disease arises from the persistent presence of cytomegalovirus (CMV) and its interaction with maladaptive innate immune responses. CMV is already implicated in age-related immune issues, so it would not be too surprising to find it causes other prevalent issues in old age.
The emergence of single nucleus RNA sequencing (snRNAseq) studies of Alzheimer's disease (AD) and aging-affected brain tissue has demonstrated the powerful opportunity for cell transcriptomics to illuminate and resolve disease mechanisms. Using 101 (AD n = 66, aged controls n = 35) exceptionally well-characterized, aged subjects from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND)/Brain and Body Donation Program (BBDP), We identified a differentially abundant AD-associated CD83(+) microglial subtype, detected in 47% of AD subjects and 25% of clinically and neuropathologically unaffected controls.
Given that CD83 is a marker of mature dendritic cells, with complex, bidirectional interactions with diverse pathogens and its role in activated microglia during neuroinflammation, we hypothesized that CD83(+) AD subjects may differ from CD83(-) AD subjects on the basis of a microbial or immunological perturbation. Mass spectrometry proteomics data from frozen transverse colon (TC) samples collected from a subset of 26 subjects revealed the most differentially abundant protein in subjects with CD83(+) microglia was immunoglobulin heavy constant gamma 4 (IGHG4) which forms the constant region of the immunoglobulin IgG4 antibody heavy chain. This observation was suggestive of increased IgG4 tissue response in the TC of AD subjects with CD83(+) microglia and more broadly, consistent with a potential microbial interaction between components of the gut microbiome and the presence of CD83(+) microglia.
We report a series of significant associations linking CD83(+) microglia in the superior frontal gyrus (SFG) with IgG4 and human cytomegalovirus (HCMV) presence in the TC, anti-HCMV IgG4 antibodies in the CSF, and both IgG4 and HCMV in the vagus nerve and SFG. HCMV histochemistry is consistent with an active HCMV infection. 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 infection.