Association Between Viral Exposures and Neurodegenerative Disease Risk

Levine and associates have published the results of a systematic investigation into the association between viral infections and neurodegenerative diseases. The large study involved data from about 400,000 controls and about 40,000 patients from the UK (UK Biobank) and Finland (FinnGen). They ultimately identified 45 viral exposures that were significantly associated with an increased risk of neurodegenerative disease and replicated 22 of the associations. Diseases included generalized dementia, which comprised the largest group, followed by Alzheimer’s disease (AD), vascular dementia, Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

The strongest association was between viral encephalitis and AD, with a hazard ratio of 30.72. The next strongest association was seen between generalized dementia and viral encephalitis, viral warts, influenza, and viral pneumonia. Influenza was associated with AD, ALS, generalized dementia, vascular dementia, and PD. Varicella zoster virus (VZV) was associated with MS and vascular dementia. Epstein–Barr virus (EBV) exposure increased the risk for MS (HR, 26.5), and EBV exposure 5 to 15 years earlier increased risk for dementia (HR, 9.00). Meningitis 5 to 15 years earlier increased risk for AD by a hazard ratio of 4.98.

The major conclusion drawn by the study is that neurodegenerative diseases can be associated with a wide variety of viral infections and no single cause could be identified. The highest association was between CNS and respiratory infections. The authors should be congratulated for undertaking such a massive study and addressing a critically important question regarding the association of viral infections and neurodegenerative diseases, which has been raised for several decades but has been mired in controversy.

Most studies have addressed the potential role of single pathogens, and collectively several infections have been implicated in these diseases. One possibility is that none of these infections causes these diseases but rather any infection can unmask an underlying neurodegenerative disease or accelerate its course. This is a major concern with the current SARS-CoV-2 pandemic as well. With nearly 700 million people infected worldwide, are we at risk of seeing a growing population with neurodegenerative diseases as well? Major efforts are needed to develop safe and effective vaccines and antiviral compounds since the long-term consequences of inaction could be dire.

Although there are many limitations that make it hard to interpret the findings, the broad implications of this study are still valid. Yet, it is important to understand the limitations of such studies. The history of infections and neurological diseases is obtained from discharge diagnoses and billing codes; hence, the accuracy of the diagnosis cannot be established. For example, the term dementia is often used for loss of cognitive function and could encompass a wide variety of neurological diseases including AD, vascular dementia, or even some cases of PD and ALS/frontotemporal dementia (FTD). Further, the stringency of the infectious etiologies is also not clear. For example, influenza seems to be a major contributor; but, if the diagnosis was made clinically without a virological assay, almost any respiratory pathogen could be called influenza since these pathogens are clinically hard to distinguish from one another. If a diagnosis is made retrospectively, then it would be subject to recall bias. Hence, one worries that neither the neurological diagnosis nor the infectious agent in many cases can be conclusively established.