This study showed that the new-onset incidence of all types of dementia and each type of AD or VD were significantly higher in subjects with CMV tissue-invasive end-organ disease. After adjusting for age, sex, low-income status, NIDDM, hypertension, and dyslipidaemia which can be the risk factors of dementia [5, 6], patients diagnosed with CMV disease had a higher risk for VD than for AD (OR, 3.3 vs. 1.7). Previous studies suggested that Helicobacter pylori, Chlamydia pneumoniae, and human T-lymphotropic virus-1 infection could be associated with VD [22-24]. The chronic infection of murine CMV (MCMV) in blood vessel could progress atherosclerotic plaque, and then VD could be induced by atherosclerosis pathogenesis in mouse model [25]. However, it is difficult to simulate the pathogenesis of HCMV disease in a MCMV infection mouse model because human CMV and MCMV are genetically different, and mice could not be infected with HCMV [26]. Even though the relevant infectious agents of VD have not been studied more than those of AD, the stronger association of CMV disease with VD than AD in this study will be interesting finding. This result suggests that CMV may play a possible role in complex VD pathogenesis because active recurrent intermittent CMV replication and/or latent CMV infection status is associated with chronic inflammatory atherosclerosis, vascular damage, and ultimately, cerebrovascular/cardiovascular diseases (CVDs) [27, 28].
Apolipoprotein E (APOE), produced in the kidney, liver, and brain, is involved in lipid transport and uptake [3, 29, 30]. The ε4 allele of APOE, a genetic risk factor for AD and CVD, induces oxidative damage in the central nervous system in herpes simplex virus infection. Neurotoxicity and neuroinflammation by APOE ultimately results in neurodegeneration and dementia [3, 30, 31]. When APOE ε4 is expressed, β-amyloid is aggregated in the brain, and amyloid plaques can cause cerebral amyloid angiopathy [32]. CMV and β-herpesviridae might also be associated with APOE. Further studies are required to evaluate the expression of the APOE genotype in dementia patients with CMV tissue-invasive disease. Generally, persistent systemic infection and inflammation can cause chronic neurodegeneration. Particularly, decreased CD8+ T lymphocyte counts and cognitive dysfunction due to CMV infection are characteristic features of AD [33-35].
Because AD is also associated with aging, age matching was essential for determining the association between the case and control groups. The IR of AD in the case group was higher in those aged 40–59 years than in those aged ≥60 years. Early-onset dementia in individuals aged <65 years was associated with head trauma, alcohol abuse, and human immunodeficiency virus-1 infection [36]. The association between CMV serostatus or disease and new-onset dementia has not been studied yet. However, one study revealed that cognitive impairment was six-times higher in patients with three risk factors of low educational level, APOE ε4 allele, and Herpesviridae including CMV infection [37]. Moreover, the APOE ε4 allele was associated with new-onset AD or a decline in cognition in the earlier clinical stages [38-41].
Since VD and AD have different pathogeneses, their time of onset may differ. According to the Kaplan-Meier curves adjusted by age and sex, AD occurs in a relatively later clinical stage after the diagnosis of CMV disease than VD. The possible pathogenesis of AD arising from deposition of amyloid plaques as a result of chronic CMV infection could explain that AD occurs in the later clinical stage [32].
This study could have the potential bias associated with the registry-based data and the heterogeneous case population that may present with neurobehavioral disturbances mimicking dementia (e.g. long-term metabolic encephalopathy in the immunocompromised patients and non-immunocompromised critically ill patients). The patients at risk of CMV reactivation may also have reactivation of other herpes virus. In addition, our report has some limitations. It was conducted using retrospective data from the NHID; thus, information on standard global measurements of cognitive function, such as the Mini-Mental Status Examination, Clinical Dementia Rating, or Activities of Daily Living, was unavailable. Inflammation markers (interferon-gamma, tumour necrosis factor-alpha, and interleukin-6) could not be analysed. Future prospective analyses can significantly support the investigation of pathogenic mechanisms of CMV infection or diseases affecting the development of each dementia type. The incidence or causes of dementia may differ by race, but we only identified the characteristics of dementia in the Republic of Korean subjects. Finally, the incidence of other types of dementia, frontotemporal dementia or Lewy body dementia, was significantly low to be included in the analysis.
However, this study had some strengths. First, only patients diagnosed with tissue-invasive end-organ diseases were included in the case group, regardless of CMV serostatus. This is a major distinctive characteristic of this study. The serum CMV IgG titre can vary at different time-points in each individual, and a positive/negative result only represents latent status caused by past CMV infection instead of representing active CMV replication. Second, we employed a nationwide population-based study using a huge database to analyse the effect of CMV on new-onset dementia after CMV diagnosis through the washout period. Third, previous studies did not include the time of dementia occurring during the follow-up. However, we analysed the onset time for dementia after CMV disease diagnosis for a relatively long duration of 7 years.