Associations of Inherited Chromosomally‐Integrated Human Herpesvirus 6 With Dementia Incidence, Inflammation, and Other Dementia Risk Factors in the UK Biobank

The infection theory of dementia states that viral infections and chronic inflammation play a role in its pathogenesis. We aimed to test whether testing positive for inherited chromosomally‐integrated human herpesvirus 6 (iciHHV‐6) is associated with an increased dementia incidence, inflammation, and other dementia risk factors. We included n  = 247,731 participants of the UK Biobank in the analysis, of whom n  = 3388 (1.4%) tested positive for iciHHV‐6. Linear and logistic regression models were performed to assess the associations between iciHHV‐6 with HHV‐6 antigens, blood‐based biomarkers of inflammation, and other dementia risk factors. Cox proportional hazards regression models were applied to assess the associations of iciHHV‐6 with all‐cause dementia, Alzheimer’s disease (AD), and vascular dementia (VD). Subjects with iciHHV‐6 exhibited statistically significantly higher antibody responses to the HHV‐6 antigens IE1A ( p  = 0.002) and IE1B ( p  < 0.001). IciHHV‐6 positivity was significantly more frequent among subjects with European or Chinese ethnicity, with lower education, higher alcohol consumption, current smoking, and longer telomere length. Interestingly, iciHHV‐6 positive subjects had lower C‐reactive protein (CRP) levels ( p  = 0.029). All other inflammatory biomarkers did not differ according to iciHHV‐6 status. Overall, 6615 participants were diagnosed with all‐cause dementia during a median of 13.6 years, including 3340 with AD and 1708 with VD. There was no significant association between iciHHV‐6 positivity and the risk of any dementia outcome. IciHHV‐6 positivity was not a risk factor for dementia outcomes or increased inflammation in this large study, but was associated with higher antibody responses against HHV‐6 antigens, ethnicity, telomere length, and lifestyle factors.