Investigation of the association between the antibody responses to neurotropic viruses and dementia outcomes in the UK Biobank
Open accessAbstract
The causes that trigger the onset of dementia are still unknown. Recently there has been an increasing interest in the possible role of infectious agents in the brain in the pathogenesis of this condition. Amongst the viruses, members of the Herpesviridae family, namely herpes simplex virus-1 (HSV1), cytomegalovirus (CMV), human herpesvirus-6 (HHV6), human herpesvirus-7 (HHV7) and varicella zoster virus (VZV) have been suggested as potential causes of the disease. However, the relative importance of these and other viruses in contributing to dementia remains unclear. We evaluated the association between seropositivity status of all viruses available in a large, population-based dataset (the UK Biobank) and dementia risk in an unbiased way. Of the 15 viruses investigated, our results showed a statistically significant increase of dementia risk associated only with HSV1 seropositivity (OR 2.14, 95% C.I. 1.21–3.81). However, by combining the data we found that seropositivity for 4 viruses (HSV1, HHV6, HHV7 and VZV) also significantly increases the risk of dementia (OR = 2.37, 95% C.I. 1.43–3.92). These four viruses have been described previously as neurotropic viruses. Our results provide support for a role for neurotropic viruses in the pathology of dementia.
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HHV6 seropositivity does not appear to be related to AD risk, although HHV6 titers among individuals co-infected with HSV-1 can be associated with increased risk of all-cause dementia.
“HHV6 seropositivity does not appear to be related to AD risk, although there is evidence that HHV6 titers among individuals co-infected with HSV-1 can be associated with increased risk of all-cause dementia [25].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [25]
The Results (page unavailable) report only a marginal association between overall HHV6 seropositivity and all-cause dementia, and an increased dementia risk for people seropositive for four viruses, including HHV6 and HSV1. The paper does not establish the claim about HHV6 seropositivity and AD risk, or report that HHV6 titers specifically predict dementia among people co-infected with HSV1; its Methods describe using binary seropositivity variables. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSome studies have failed to find a link between VZV and AD, including those that utilize electronic health records or titer measurements.
“However, some studies have failed to find a link between VZV and AD, including those that utilize electronic health records or titer measurements [25,41,42].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [25]
The Results (Table 2, page not provided) report that VZV seropositivity was not significantly associated with dementia after adjustment (OR 3.38, 95% CI 0.83–13.78; p=0.089), supporting the limited point that this study did not establish a link for VZV alone. The paper studied dementia rather than AD specifically and used antibody seropositivity, not titer measurements or electronic health records. It describes the VZV result as a marginal association, not an absence of evidence for a link. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA link between HSV-1 seropositivity and AD has been found, and a recent prospective cohort study showed HSV-1 infection can double AD risk.
“On the one hand, a link between HSV-1 seropositivity and AD has been found, and a recent prospective cohort study showed HSV-1 infection can double AD risk [25,26].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [25]
The Results (Association between seropositivity status and dementia risk; page unavailable) report an association between HSV-1 seropositivity and dementia (OR 2.14), but do not give that estimate for Alzheimer’s disease specifically. The Discussion describes prospective-cohort evidence of increased AD risk only among APOE-ε4 carriers with particular antibody findings; it does not report a doubling of AD risk in that cohort. (LLM, conf=0.88)
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UK Biobank: From Concept to Reality
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What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease?
Brutkiewicz, R. R., Cao, W., Morgan, D., Reis, R. S. D., Suryadevara, V., Willette, A. A., Willette, S. A., Wyatt-Johnson, S. K., & Duggan, M. R. (2025) · Trends in Neurosciences · doi:10.1016/j.tins.2025.05.009 · Cited by 3 · see citing works
- Authors
- Mekli, K., Lophatananon, A., Cant, R., Burns, A., Dobson, C. B., Itzhaki, R. F., & Muir, K. R.
- Affiliations
- University of Manchester (GB)
- University of Oxford (GB)
- Corresponding author
- Muir, Kenneth R.
- ORCID
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2022-10-12
- Volume
- 17
- Issue
- 10
- Pages
- e0274872
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC9555633
- OpenAlex
- W4304701148
- Cited by
- 25
- References
- 4
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 4 · 2023: 4 · 2021: 1
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Engineering and Physical Sciences Research Council (EP/N510129/1)
- The Advantage Foundation (EP/N510129/1)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Keywords
- dementia, neurotropic viruses, herpesvirus, herpes simplex virus type 1, cytomegalovirus, human herpesvirus 6, human herpesvirus 7, varicella-zoster virus, seropositivity, dementia risk, UK Biobank
- MeSH terms
- Antibody Formation, Dementia, United Kingdom, Humans, Herpesvirus 3, Human, Herpesvirus 6, Human, Herpesvirus 7, Human, Biological Specimen Banks, Herpesvirus 1, Human
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