Readhead BP, Mastroeni DF, Wang Q, Sierra MA, de Ávila C, Jimoh TO, Haure-Mirande JV, Atanasoff KE, Nolz J, Suazo C, Barton NJ, Orszulak AR, Chigas SM, Tran K, Mirza A, Ryon K, Proszynski J, Najjar D, Dudley JT, Liu ST, Gandy S, Ehrlich ME, Alsop E, Antone J, Reiman R, Funk C, Best RL, Jhatro M, Kamath K, Shon J, Kowalik TF, Bennett DA, Liang WS, Serrano GE, Beach TG, Van Keuren-Jensen K, Mason CE, Chan Y, Lim ET, Tortorella D, Reiman EM. Alzheimer's disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain. Alzheimers Dement. 2025 Jan;21(1):e14401. Epub 2024 Dec 19 PubMed.
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Philadelphia College of Osteopathic Medicine
This article provides an intriguing insight into infection with human cytomegalovirus and its connection with Alzheimer’s disease. The work further supports an infectious process that can result in specific changes in the brain and relevant cell types consistent with the pathogenesis process of AD (Itzhaki et al., 2016). Involvement of the gut and brain changes and infectivity in both areas highlights features of the gut-brain axis that may be important for general consideration in infection-related neurodegenerative conditions.
While this report focuses on one infectious agent involved in disease, many of us, as part of the Alzheimer’s Pathobiome Initiative, have been studying infection in AD for decades (Lathe et al., 2023; Bathini et al., 2024), and realize that we need to consider a polymicrobial approach to understanding the wide-ranging relationships of infections with AD as well as the many other neurodegenerative diseases. These findings are very important in the sense that infections may be early upstream drivers of disease. We need to focus on how to more precisely diagnose what may be onboard prior to disease onset, and to intervene, if possible, with appropriate drug regimens. In this regard, there are notable cases of “reversible dementias” for which an infectious agent was determined to be present, followed by precise therapeutic interventions to effectively treat (Lathe et al., 2023).
Intriguingly, the findings of HCMV associated with CD83+ microglia in the superior frontal cortex but not reported for other brain regions leads one to consider that different brain regions and cells therein may be insulted with different microbial organisms with varying degrees of virulence. Furthermore, the routes of infections into the brain need to be considered in regard to the different organisms that have been associated with AD and other neurological conditions. For example, respiratory organisms may use the olfactory system for uptake and further brain involvement, whereas those infecting other sensory systems such as vision and hearing could use other cranial nerve involvement, much like gut organisms using the vagal nerve for potential uptake (Bathini et al., 2024).
Other important considerations with regard to infections as drivers of AD pathogenesis are selective vulnerability in brain regions and genetic predisposition. As a number of the neurodegenerative conditions appear to start in discrete brain regions, a consideration of structure to function relationships can provide clues as to where an infectious insult may be principally important. Genetic predispositions may include those such as the APOE genotype and HLA expression.
The overall message from studies such as this is that we need to study the relationships between infection (often chronic, persistent, latent) within the nervous system and neurological insult, because they go well beyond our recognition of the typical designations of meningitis, encephalitis, meningoencephalitis.
References:
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View all comments by Brian BalinOHSU
In this original and timely study, Readhead et al. followed up on their earlier data showing that an AD-related CD83(+) microglia subtype associated with increased immunoglobulinG4 (IgG4) in the transverse colon (Wang et al., 2024). In the current study, CD83(+) microglia in the superior frontal gyrus were associated with elevated levels of IgG4 and human cytomegalovirus in the TC, anti-HCMV IgG4 in CSF, and HCMV and IgG4 in the SFG and vagal nerve. In addition, HCMV-infected cerebral organoids showed enhanced AD pathology, namely Aβ42 and pTau-212, and neuronal death. The CD83(+) microglia might not be specific to AD, as they were also noted in the EAE multiple sclerosis model (Sinner et al., 2023). The association between viruses and AD is not limited to HCMV and has been proposed for reactivated Herpes Simplex (Itzhaki, 1994) and other neurotropic viruses as well; the viral association is not limited to AD, either, but has been made with other neurodegenerative conditions (Levine et al., 2023).
While HCMV is very common in the blood in the elderly, HCMV in the TC is not (Chen et al., 2021). HCMV in the TC is associated with CD83(+) microglia and HCMV in the SFG, supporting key roles for the gut microbiome and gut-liver-brain axis in AD. Consistent with such roles, Ferreiro et al. reported that in cognitively healthy 68- to 94-year -olds, there are gut-microbiome correlates of preclinical AD neuropathology (Aβ and tau biomarkers), and that inclusion of microbiome features that associated with preclinical AD improved prediction of preclinical AD status (Ferreiro et al., 2023). In addition, the human gut microbiome diversifies with age, reflects healthy vs. unhealthy aging, associates with a healthy lipid profile, and predicts survival (Wilmanski et al., 2021), while alterations in microbiome composition have been linked to AD and impact AD-associated behaviors and brain pathologies (Kundu et al., 2022; Kundu et al., 2021; Marizzoni et al., 2020).
That HCMV-infected cerebral organoids enhance Aβ42 and p-tau212 supports a causal role of viral infection in AD pathology. As the gut-liver-brain axis is bi-directional, it is not clear yet whether, in the case of HCMV, viral replication and/or reactivation is originally or mainly driven by the gut and/or brain. Regardless, given other studies supporting the role of the gut microbiome in AD mouse models (Kundu et al., 2021), AD, and Parkinson’s disease (Santos et al., 2019; Elfil et al., 2020; Keshvarzian et al., 2020; Koutzoumis et al., 2020; Sampson et al., 2016; Torres et al., 2018), increased efforts are warranted to better understand the role of (re)activation of neurotropic viruses and associated inflammation and AD pathology in the gut, and whether antivirals and/or other microbiome-targeted strategies can delay or even prevent incidence or severity of AD.
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View all comments by Jacob RaberSwiss Integrative Center for Human Health
The growing body of literature linking herpesviruses to neurodegenerative processes has evolved from observational cohort studies to mechanistic experimental research. Observational studies have shown that antiherpetic drugs are associated with a reduced risk of developing neurodegenerative dementias such as Alzheimer's disease. Experimental models have provided complementary evidence, with herpes simplex virus 1 (HSV-1) shown to induce Aβ aggregation in vitro and in vivo. Readhead et al.’s findings extend this research by implicating human cytomegalovirus in AD pathology through cross-tissue immunological mechanisms involving CD83(+) microglia and immunoglobulin G4 (IgG4) responses. This study's integration of histological, immunological, and transcriptomic data reinforces the infectious hypothesis in AD, supporting a more comprehensive, mechanistically driven model of herpesvirus-induced neurodegeneration.
Herpesviridae are widespread in the human population, yet only a subset of individuals experience viral reactivation and increased neurodegenerative risk. While immunosuppression is a well-recognized trigger, as seen in shingles outbreaks among immunocompromised individuals, the exact mechanism remains unclear. Reactivation may be influenced by viral latency reservoirs, chronic inflammation, and cellular senescence. Readhead et al. propose that HCMV persistence in gut tissues could enable periodic reactivation, facilitated by immunosenescence or gut-brain axis dysfunction. However, broader investigations into viral strain variations, host immune-genetic factors, and co-infections are warranted. Indeed, pathogenic symbiosis of HCMV with HSV-1 (Lövheim et al., 2018) or EBV (Torniainen-Holm et al., 2018) has been previously reported and other pathobiont species have been implicated besides Human Herpesviridae (Zilli et al., 2021). In practical terms, the investigation of polymicrobial infections (bacterial, viral and fungal) is multidimensional, requiring a multipronged effort, such as the one from the Alzheimer’s Pathobiome Initiative, a research consortium committed to unravel and translate the infectious etiology of AD.
Nevertheless, the study highlights HCMV as the primary viral agent inducing AD-like neuropathology in cerebral organoids, while noting that lipopolysaccharide (LPS) and human herpesvirus 6A (HHV-6A) failed to produce similar effects. This contrasts with prior research where LPS-induced AD-like pathology (Zhan et al., 2018) while HHV-6A’s subtler contributions to neuroinflammation are documented. This discrepancy might be attributable to the specific cellular composition of the organoid models used or to differences in viral titers and infection protocols. Expanding to more diverse in vitro models could clarify these differential responses.
The study proposes a gut-brain axis mediated by the vagus nerve as a plausible gateway for HCMV entry into the brain, supported by histological evidence of viral presence along this route. This explanation may be incomplete. HCMV is known to establish latency in hematopoietic progenitor cells and endothelial tissues, suggesting that alternative routes such as hematogenous dissemination through infected monocytes could also play a role, particularly in conditions of endothelial permeability and vascular damage. Future work should consider multi-organ viral dynamics to build a more comprehensive model of central nervous system (CNS) invasion.
An important contribution of this study is the identification of HCMV-specific IgG4 antibodies, implicating a potential viral immune evasion strategy. IgG4’s known anti-inflammatory properties may facilitate chronic viral persistence by dampening host immune responses. Understanding how IgG4-driven immune suppression influences both viral reactivation and neurodegeneration could open new therapeutic avenues, including immunomodulatory treatments targeting the adaptive immune system.
These findings add to the increasing and highly debated literature implicating microbial infections in Alzheimer’s disease (AD) etiology. From Ruth Itzhaki’s pioneering work linking HSV-1 to AD pathology (Itzhaki et al., 1997; Itzhaki, 2021), 30 years of research have explored microbial neurotropism, particularly Herpesviridae. Observational studies showed antiherpetic drugs reduce dementia risk (Tzeng et al., 2018; Lövheim et al., 2019; Schnier et al., 2021), but enthusiasm for these treatments has been lukewarm due to skepticism about causality. Recent experimental evidence—such as HSV-1’s ability to induce Aβ aggregation as an antimicrobial trap—has shifted the conversation toward antiviral interventions (Eimer et al., 2018). However, funding challenges persist, limiting deeper exploration of microbial or polymicrobial triggers.
Readhead et al.’s untargeted search for HCMV reactivity in AD brains represents a less-biased approach that aligns with prior studies often dismissed as exotic. Herpesviridae’s ubiquity complicates public health implications, as reactivation risks remain poorly understood. Addressing reactivation mechanisms requires personalized approaches that may be resource-intensive. Nevertheless, vaccines like BCG (against M. tuberculosis) (Weinberg et al., 2023) or Shingrix (against VZV)—shown to reduce inflammation and viral reactivation—could prevent cascades leading to neurodegeneration, including chronic inflammation and blood-brain barrier permeability.
The possibility that microbial reactivation occurs decades before cognitive symptoms underscores the need for early intervention. Precision medicine using artificial intelligence to identify individual risk trajectories could redefine preventive strategies. Bold investment in alternative therapeutic mechanisms, including infection-focused approaches, is crucial for advancing AD treatment paradigms.
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