Potential neuroinflammatory outcomes following infection.
#18,762
In the decade following the 1918 influenza pandemic the world saw a secondary global rise of neurodegenerative diseases - including Parkinson's and what we would describe today as Alzheimer's Disease (AD) - that was dubbed Encephalitis lethargica (EL) (aka "sleeping sickness").While some scientists believed (EL) was a rare sequelae of the 1918 pandemic virus, the exact cause remains unknown. A post-viral infection, however, remains a likely culprit (see Evidence for an enterovirus as the cause of encephalitis lethargica).
Regardless, millions died, or were institutionalized.
Throughout history, there have been reports of other neurological outbreaks following severe epidemics, including febris comatosa which sparked a severe outbreak in London between 1673 and 1675, and following the 1889–1890 influenza (?) pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") was described in Italy.
Although the exact cause of the 1889-1890 pandemic remains unknown (candidates include H3N8, H2N2, and potentially, a SARS-like coronavirus), it is often cited as causing unusual neurological manifestations.
This history of post-pandemic neurological sequelae sparked discussions early in the COVID pandemic (see J. Neurology: COVID-19 As A Potential Risk Factor For Chronic Neurological. Disorders), and we continue to see worrisome signs today (see Long-term Neurological and Cognitive Impact of COVID-19: A Systematic Review and Meta-analysis in over 4 Million Patients).
Increasingly, we see concerns that neurodegenerative diseases may be caused - or at least, exacerbated - by past bacterial or viral infections (see Alzheimer's Society Infections and the risk of dementia)
A study published a little over two years ago in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, found statistical linkage between viral illnesses and developing neurodegenerative diseases later in life.
Today we have an article published this week in Aging Neuroscience which reviews the evidence linking two respiratory pathogens (Chlamydia pneumoniae and SARS-CoV-2) to Alzheimer’s disease (AD) development and progression.
With the very strong caveat that the exact cause of Alzheimer's, Parkinson's, and other neurogenerative diseases are not yet known - and all are likely the result of multiple genetic and environmental factors - the role of infectious diseases is a hypothesis under serious investigation.
The author's of today's review paper offer a plausible hypothesis on how some types of viral and bacterial infections could potentially contribute to the pathogenesis of Alzheimer's Disease.
I've posted the link, and some excerpts, but you'll want to read review in its entirety. I'll have a brief postscript after the break.
Infections with Chlamydia pneumoniae and SARS-CoV-2 and Alzheimer’s disease pathogenesis
Alexa Romanella, 1Maegan McCall2, Rachel Corwin1, Alaha Abdul Faruq1, Emily Lingo1, Sanya Bhambhani1, Christine J. Hammond3,
Introduction: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the world, but our understanding of causation is still lacking. A current evidence-based hypothesis proposes that certain infectious agents initiate the neurodegeneration consistent with AD. Two infectious agents correlated to AD pathogenesis are Chlamydia pneumoniae (Cpn), a respiratory obligate intracellular bacterium, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus responsible for the COVID-19 pandemic. Both organisms may predispose susceptible populations to disease manifestations, such as AD.
Methods: This review focused on peer-reviewed original research and review articles evaluating the potential association of Cpn and SARS-CoV-2 with AD. Our focus included: genetic risk with expression of APOEε4 and other biomarkers common to AD including interleukin-6 (IL-6), chemokine ligand 2 (CCL2), neuropilin-1 (NRP1), and structural/functional aspects of the infectious processes and resultant neuroinflammation.
Results: Both Cpn and SARS-CoV-2 may infect the neuroepithelium of the olfactory system to enter the brain. Cpn binds to heparan sulfate proteoglycans for entry into mucosal cells. SARS-CoV-2 infects epithelia after binding to ACE2 receptors. Once inside the neuroepithelium, the pathogens may traffic to the olfactory bulbs. NRP1, an abundant receptor in AD, also potentiates SARS-CoV-2 infection. Furthermore, both pathogens may enter the systemic circulation for eventual entry through the blood brain barrier. The SARS-CoV-2 spike protein, in conjunction with CCL2, co-stimulates macrophages, resulting in IL-6 cytokine release. Likewise, Cpn infection leads to an increase of CCL2 and IL-6 cytokine release. The primary infection of either organism may lead to chronically elevated levels of IL-6 and secondary infection(s). Additionally, host APOEε4 expression appears to increase susceptibility to Cpn and SARS-CoV-2 infections.
Discussion: Cpn and SARS-CoV-2 may enter the brain through olfactory neuroepithelial cells and/or through the blood brain barrier. SARS-CoV-2 utilizes specific receptors for infection, while Cpn utilizes binding of proteoglycans. Neuroinflammation may be an outcome of infection with one or both organisms as observed by increased levels of CCL2 and IL-6 leading to AD pathogenesis. Genetic risk is noted for infection with both organisms with expression of APOEε4. Ongoing and future studies will further dissect mechanisms of infection with SARS-CoV-2 and Cpn as they may inform on causation and diagnostic factors for AD.
(SNIP)
Infection with SARS-CoV-2 or Cpn may contribute to AD pathogenesis
While the exact pathology of AD is unclear, there is evidence to suggest that its development may be linked to inflammation of neuronal tissue, specifically in the limbic system.
There are many situations that can cause neuroinflammation, one being infection with microbes that are able to gain entrance to the CNS. We have described a few pathways by which Cpn and SARS-CoV-2 can gain entry to the CNS and proceed to promote inflammation via modulation of an inflammatory cascade.
We therefore propose that in certain settings, such as with aging and genetic predisposition, that infection with these pathogens may be a risk factor for the development or modulation of AD.
As an EMT/Paramedic in the 1970s who saw a lot of senile dementia patients - and whose grandfather died of Parkinson's in the 1960s - I've often wondered about the potential link between the 1918 pandemic (when most of my patients would have been young adults or teenagers) and neurodegenerative diseases.
Whether that question will be definitively answered before I exit this mortal coil remains to be seen.
But recent studies suggest the fewer viral or bacterial assaults you endure, the less likely you are to develop a neurodegenerative disease. Which is one of the reasons why - in 2025 - I continue to mask up when in crowded public spaces and stay current with my flu and COVID vaccines.
And quite honestly, I can't imagine changing that anytime soon.
