Key findings from Liu et al. 2025
#18,902
One hundred years ago the world was in a post-pandemic era following the end of the 1918 Spanish Flu, but found itself struggling with a new, mysterious, and devastating neurodegenerative malady called Encephalitis Lethargica (EL)
It has been estimated that as many as 5 million people were afflicted with EL between 1917 and 1927 - and while roughly 1/3rd died during the acute phase of the illness - many of the survivors would go on to develop Parkinsonian features and other profound neurological sequelae, often years later.
The exact cause remains unknown, but many have speculated it was due to past exposure to the Spanish flu, or to some other viral infection (see Evidence for an enterovirus as the cause of encephalitis lethargica).
Throughout history, there have been reports of similar outbreaks, resulting in severe neurological disease, including febris comatosa which sparked a severe epidemic in London between 1673 and 1675, and in 1890 in Italy, in the wake of the 1889–1890 influenza pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") appeared.
While the reason behind these epidemics remains elusive, a virus - or perhaps an autoimmune response to a viral infection - are both plausible suspects.
BMC Neurology: Long-term Neurological and Cognitive Impact of COVID-19: A Systematic Review and Meta-analysis in over 4 Million Patients
In early 2023, in Neuron: Virus Exposure and Neurodegenerative Disease Risk Across National Biobanks, we looked at a large study, published in Cell Neuron, which found a statistical linkage between viral illnesses and developing neurodegenerative diseases later in life.
While we don't have a smoking gun, adding the to the preponderance of evidence we have the following meta-analysis - published yesterday in Nature - with cites an 88% increase in the risk of developing Alzheimer's Disease following COVID infection (OR = 1.88; 95% CI: 1.53, 2.32).
The caveat here is; although many studies have found associations between viral infections and neurodegenerative processes - due to varying study designs, the cohorts studied, differences in statistical controls, etc. - they don't all show the same increases for the same viruses.
The reality is: we are likely not dealing with a single “neurodegeneration virus”, but rather with multiple viral agents that are capable of causing neuroinflammation and/or and protein misfolding across some percentage of the population.
Due to its length, I've only reproduced the abstract. Follow the link to read it in its entirety. I'll have a brief postscript after the break.
Viral infections and the risk of neurodegenerative diseases: a comprehensive meta-analysis and systematic reviewRu-Yin Liu, Kang-Fu Yin, Sheng-Yi He, Wei-Ming Su, Qing-Qing Duan, Xiang-Jin Wen, Ting Chen, Cong Shen, Ju-Rong Li, Bei Cao & Yong-Ping Chen
Translational Psychiatry volume 15, Article number: 388 (2025)
Abstract
Background
Viral infections have been implicated in the pathogenesis of neurodegenerative diseases (NDs); however, evidence linking specific viruses to Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) remains inconclusive. This study conducted a meta-analysis and systematic review to investigate these associations.
Methods
Thorough searches were conducted across Embase, PubMed, Cochrane Library, Web of Science and Scopus until May 18, 2025, to identify observational studies investigating the relationship between viral infections and the risk of NDs, including AD, PD, and ALS. Meta-analyses were executed using a random-effects model with Stata MP18.0.
Results
A total of 34,417 articles were identified, of which 73 met the eligibility criteria for inclusion in the meta-analysis, and 48 were included in the systematic review. The analysis demonstrated that infections with cytomegalovirus (CMV) (odds ratio [OR] = 1.41; 95% confidence interval [CI]: 1.03, 1.93), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (OR = 1.88; 95% CI: 1.53, 2.32), hepatitis C virus (HCV) (OR = 1.39; 95% CI: 1.14, 1.69), and human herpesvirus (HHV) (OR = 1.24; 95% CI: 1.02, 1.51) were associated with an increased risk of AD. Regarding PD, infections with hepatitis B virus (HBV) (OR = 1.18; 95% CI: 1.04, 1.35) and HCV (OR = 1.29; 95% CI: 1.18, 1.41) were identified as risk factors. Conversely, no significant correlation was found between any viral infection and the risk of ALS.
Conclusion
This meta-analysis supports the role of select viral infections in AD and PD pathogenesis. However, no association was found be tween viral infections and ALS, warranting further large, multicenter, and longitudinal studies to elucidate mechanisms and confirm causality.
While the data we have is far from conclusive, we've seen mounting evidence suggesting that certain viral infections - including COVID-19 - are credible long-term neurological threats.
Importantly, we also continue to see evidence (see Preprint: Incidence of Long COVID Following Reinfection with COVID-19) that repeated COVID infections only increase the risks of lasting sequelae.
Which is why last weekend I got my updated COVID shot and my seasonal flu shot (different arms) from my local pharmacist. While these vaccines may not always prevent infection - they can often greatly reduce their severity - and hopefully, any lasting neurological impacts.
And given the stakes - for me, at least - it seems like cheap insurance.
