The Role of Chronic Infection in Alzheimer's Disease: Instigators, Co-conspirators, or Bystanders?

Abstract

Purpose of review: Herein, we provide a critical review of the clinical and translational research examining the relationship between viral and bacterial pathogens and Alzheimer's disease. In addition, we provide an overview of the biological pathways through which chronic infection may contribute to Alzheimer's disease.

Recent findings: Dementia due to Alzheimer's disease is a leading cause of disability among older adults in developed countries, yet knowledge of the causative factors that promote Alzheimer's disease pathogenesis remains incomplete. Over the past several decades, numerous studies have demonstrated an association of chronic viral and bacterial infection with Alzheimer's disease. Implicated infectious agents include numerous herpesviruses (HSV-1, HHV-6, HHV-7) and various gastric, enteric, and oral bacterial species, as well as Chlamydia pneumonia and multiple spirochetes.

Summary: Evidence supports the association between multiple pathogens and Alzheimer's disease risk. Whether these pathogens play a causal role in Alzheimer's pathophysiology remains an open question. We propose that the host immune response to active or latent infection in the periphery or in the brain triggers or accelerates the Alzheimer's disease processes, including the accumulation of amyloid-ß and pathogenic tau, and neuroinflammation. While recent research suggests that such theories are plausible, additional longitudinal studies linking microorganisms to Aß and phospho-tau development, neuroinflammation, and clinically defined Alzheimer's dementia are needed.

Keywords: Alzheimer’s disease; bacterial infection; chronic infection; dementia; neuroinflammation; viral infection.

Figure 1.

There are at least three hypotheses which characterize the potential relationship between chronic infection and Alzheimer’s disease (AD). Hypothesis 1, also described as the “infectious origin” hypothesis, posits that infectious agents can trigger AD pathogenesis. Hypothesis 2, also described as the “infectious accelerant” hypothesis, posits that infectious agents are not necessary, but can accelerate the development and progression of AD pathology. Hypothesis 3, which posits that there is no causal relationship between chronic infection and AD, suggests further that infection may be only an associative feature of AD. Figure created with Biorender.com

Figure 2.

(A) Viral and bacterial products are recognized by macrophages, neutrophils, and dendritic cells in peripheral tissues. Viral products in infected cells can be recognized by Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and retinoid acid-inducible gene-I (RIG-I)-like helicases (RLHs). Bacteria are recognized by TLRs, scavenger receptors, C-type lectins, and integrins. This recognition of pathogens by innate immune cells causes an inflammatory response characterized by the release of cytokines and chemokines, small proteins which interact with other immune cells to coordinate the inflammatory response. (B) Cytokines and chemokine released from peripheral immune cells can trigger neuroimmune activation by interacting with microglia. (C) Inflammatory cytokines can alter the microglial phenotype, promoting a shift from a homeostatic or protective/disease resolving phenotype to a cytotoxic pro-inflammatory phenotype. (D) Viral or bacterial pathogens that infiltrate the central nervous system can also be recognized by microglia. These pathogens can shift microglia toward a cytotoxic pro-inflammatory phenotype. (E) In the context of Alzheimer’s disease pathogenesis, amyloid-ß oligomers interact with TLRs and scavenger receptors on microglial cells. While microglia may initially clear brain amyloid-ß via phagocytosis, excessive amyloid-ß accumulation may promote a pro-inflammatory cytotoxic microglial response, causing tau hyperphosphorylation, neuronal synaptic dysfunction. (F) Through activation of the host immune response, chronic infection can promote atherosclerosis and endothelial dysfunction, ultimately increasing risk for cerebrovascular dysfunction, specifically thrombotic stroke. Figure created with Biorender.com.