Virus exposure and neurodegenerative disease risk across national biobanks
Open accessPublished version of a preprint
Abstract
With recent findings connecting the Epstein-Barr virus to an increased risk of multiple sclerosis and growing concerns regarding the neurological impact of the coronavirus pandemic, we examined potential links between viral exposures and neurodegenerative disease risk. Using time series data from FinnGen for discovery and cross-sectional data from the UK Biobank for replication, we identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease and replicated 22 of these associations. The largest effect association was between viral encephalitis exposure and Alzheimer's disease. Influenza with pneumonia was significantly associated with five of the six neurodegenerative diseases studied. We also replicated the Epstein-Barr/multiple sclerosis association. Some of these exposures were associated with an increased risk of neurodegeneration up to 15 years after infection. As vaccines are currently available for some of the associated viruses, vaccination may be a way to reduce some risk of neurodegenerative disease.
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Several viruses and bacteria were associated with dementia risk, and risk was elevated more in those with CNS infections but also with extra-CNS infection.
“Several viruses and bacteria were associated with dementia risk and risk was elevated more in those with CNS infections but also with extra-CNS infection. (337, 341, 342) (337)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [341]
The Results section reports replicated associations between dementia and several viral infections, including viral encephalitis, influenza, and viral pneumonia. It does not establish associations for several bacteria or directly compare dementia risk after CNS versus extra-CNS infections; the Introduction describes the bacterial evidence as inconclusive. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStudies using electronic health records have found a link between VZV and risk of all-cause dementia, AD, vascular dementia, with antivirals decreasing all-cause dementia risk.
“Studies using electronic health records have found a link between VZV and risk of all-cause dementia, AD, vascular dementia, with antivirals decreasing all-cause dementia risk [23,36–40].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [39]
The Results report a replicated association between varicella-zoster virus (VZV) and vascular dementia, but do not report a VZV infection association with all-cause dementia or AD. The Discussion says some studies suggest antivirals may reduce dementia risk in patients with VZV; it does not establish that antivirals decrease the risk. Its separate statement about reduced dementia and AD risk concerns shingles vaccination, not VZV infection. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNeurotropic pathogens such as human herpes virus, herpes simplex virus, hepatitis C virus, cytomegalovirus, varicella-zoster virus, and Epstein-Barr virus are associated with Alzheimer's disease neuropathology.
“For example, neurotropic pathogens, such as human herpes virus (HHV), herpes simplex virus (HSV), hepatitis C virus (HCV), cytomegalovirus, varicella-zoster virus, and Epstein–Barr virus are associated with Alzheimer’s disease (AD) neuropathology [10,11,12,13].”
From VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice (2024) · cites this paper as [10]
The Discussion reports literature suggesting associations of HSV encephalitis and hepatitis with AD, and EBV with dementia. The Results associate varicella-zoster virus with multiple sclerosis and vascular dementia, not AD. These passages concern disease risk rather than AD neuropathology, and do not establish the claimed associations for every listed pathogen, including cytomegalovirus. Page numbers are not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOther types of brain injuries include injuries secondary to preventable infections.
“These brain injuries include injuries secondary to preventable infections,130 which could be addressed through promotion of better vaccine uptake, hygiene, and management plans in schools and universities.”
From Next generation brain health: transforming global research and public health to promote prevention of dementia and reduce its risk in young adult populations (2024) · cites this paper as [130]
Neurotropic viruses directly invade the CNS through the blood-brain barrier and peripheral nervous system, accompanied by the SASP, activation of microglia and astrocytes, and neuroinflammation, jointly promoting neurodegeneration and cognitive impairment.
“Neurotropic virus directly invade CNS through BBB and peripheral nervous system, accompanied by the SASP, activation of microglia and astrocytes, neuroinflammation, jointly promoting neurodegeneration and cognitive impairment.342–344”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [343]
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References 39 · Cited by 341
- Authors
- Levine, K. S., Leonard, H. L., Blauwendraat, C., Iwaki, H., Johnson, N., Bandres-Ciga, S., Ferrucci, L., Faghri, F., Singleton, A. B., & Nalls, M. A.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Nalls, Mike A.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2023-04
- Volume
- 111
- Issue
- 7
- Pages
- 1086-1093.e2
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC10079561
- OpenAlex
- W4317436847
- Cited by
- 341
- References
- 39
- Citations by year
- 2026: 76 · 2025: 97 · 2024: 102 · 2023: 65 · 2021: 1
- FWCI
- 67.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by)
- medRxiv (acceptedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, other-oa)
- Funders
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke (33601)
- National Institutes of Health
- U.S. Department of Health and Human Services (ZO1 AG000535)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- viral exposure, neurodegenerative diseases, Alzheimer's disease, multiple sclerosis, Epstein-Barr virus, viral encephalitis, influenza, pneumonia, COVID-19 pandemic, biobank data, replication
- MeSH terms
- Alzheimer Disease, Cross-Sectional Studies, Herpesvirus 4, Human, Humans, Multiple Sclerosis, Biological Specimen Banks, Neurodegenerative Diseases, Epstein-Barr Virus Infections
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