Neuroinflammation in Alzheimer's Disease: A Potential Role of Nose-Picking in Pathogen Entry via the Olfactory System?

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Many possible factors might contribute to the development of AD, including amyloid peptide and tau deposition, but more recent evidence suggests that neuroinflammation may also play an-at least partial-role in its pathogenesis. In recent years, emerging research has explored the possible involvement of external, invading pathogens in starting or accelerating the neuroinflammatory processes in AD. In this narrative review, we advance the hypothesis that neuroinflammation in AD might be partially caused by viral, bacterial, and fungal pathogens entering the brain through the nose and the olfactory system. The olfactory system represents a plausible route for pathogen entry, given its direct anatomical connection to the brain and its involvement in the early stages of AD. We discuss the potential mechanisms through which pathogens may exploit the olfactory pathway to initiate neuroinflammation, one of them being accidental exposure of the olfactory mucosa to hands contaminated with soil and feces when picking one's nose.

Keywords: Alzheimer’s disease; bacteria; brain; fungi; hand hygiene; neurodegeneration; neuroinflammation; nose-picking; olfaction; viruses.

Figure 1

Chronic neuroinflammation as a critical player in pathogen-mediated neurodegeneration. Infectious agents entering the brain, facilitated by aging-related factors, including a weaker immune system and blood–brain barrier (BBB), lead to chronic neuroinflammation. As a reaction of the brain, β-amyloid (Aβ) is produced, which has antibacterial and antiviral properties. Aβ aggregates to fibrils, forming senile plaques, which can lead to neurodegeneration via direct and inflammatory action. Chronic neuroinflammation also leads to the formation of intracellular neurofibrillary tangles, with hyperphosphorylated tau as a precursor. Both senile plaques and tangles are hallmarks of AD, as well as pathogenic agents driving the neurodegenerative process. Image inspired by Vigasova et al. [27]. Figure created using Biorender, https://www.biorender.com, accessed on 22 September 2023.

Figure 2

Multiple pathogen recognition pathways may be linked to Alzheimer’s disease. This figure summarizes the key pathways identified in the literature relevant to AD. Introduction of pathogens into the nasal cavity (see pathogen introduction, top left) and subsequently to the olfactory nervous system could lead to priming of PRR signaling via Toll-like receptors, NLRP3, and the cGAS/STING pathway, which induces inflammatory cytokine production and potentially pyroptotic cells death (upper right), which may in turn lead to further inflammation and greater responses to endogenous ligands such as cytosolic DNA and amyloid (bold). Figure created in Biorender. NFTs—neurofibrillary tangles; GSDMD—gasdermin; IRF—interferon regulatory factor; IL—interleukin; TNF—tumor necrosis factor. Figure created in Biorender, https://www.biorender.com, accessed on 22 September 2023.