Observational longitudinal study finds correlation.
As summarized in other articles, there is growing evidence that infectious agents may participate in the pathogenesis of some cases of dementia. The evidence that HHV-6 may be one of these infectious agents is controversial (Komaroff 2020).
Other well-established factors also are central to the pathogenesis of dementias. Alzheimer’s disease dementia, in particular, is strongly linked not only to neuroinflammation but also to the accumulation in the brain of amyloid-ß and tau. Infectious agents can not only cause neuroinflammation but can be linked to the neuronal death that causes dementia in several ways:
- Amyloid-ß may be an antimicrobial peptide that has been evolutionarily preserved to respond to infectious agents;
- Amyloid-ß can raise levels of tau;
- Amyloid-ß, tau and neuroinflammation all can cause neuronal death; and
- Neuroinflammation can be stimulated by inflammation outside the brain (such as the lungs and gut).
Each of these factors makes plausible a role for infection in some cases of dementia.
Surely viruses that are both neurotropic and persistent—like herpesviruses—would seem to be prime candidates for inducing chronic, low-grade neuroinflammation (and increased levels of amyloid-ß and tau).
Most of the epidemiologic and laboratory studies examining the possible role of herpesviruses in the pathogenesis of the dementias have focused on herpes simplex viruses (HSV-1 and HSV-2). One large past study of over 33,000 people, some of whom had been diagnosed with clinically apparent HSV infections found an increased risk of subsequent dementia (hazard ratio of 2.6, 95% CI: 2.2-2.8) (Tzeng 2018).
Multiple past studies have examined whether another herpesvirus, varicella-zoster virus (VZV), is associated with the subsequent development of dementia. One study found a modest association (hazard ratio [HR] = 1.11; 95% CI, 1.04-1.17) (Chen 2018) whereas a meta-analysis of multiple studies of this question failed to find a statistically significant association, except when herpes zoster infection involved the eye (Tsai 2017).
A large new study of three cohorts including nearly 150,000 people who were followed for many decades found that those who developed shingles were more likely to go on to report problems remembering simple things. New medical diagnoses (including validated cases of shingles) were carefully recorded, and study subjects periodically completed questionnaires to assess subjective cognitive decline. Over more than a decade of observation, shingles was a significant predictor of dementia: relative risks, after using multivariate statistics to adjust for the impact of other factors known to affect dementia, ranged from 1.14 to 1.34, depending on the cohort, patient sex, and duration of observation—a statistically significant increased risk.
Taken together, these studies support the hypothesis that infection with three herpesviruses—HSV-1, HSV-2 and VZV—is correlated with the subsequent development of dementia. Another study finds that SARS-CoV-2 infection also is associated with an increased risk of subsequent dementia, although since reactivation of herpesviruses frequently occurs during SARS-CoV-2 infection it remains possible that the correlation between SARS-CoV-2 infection and subsequent dementia may occur because of reactivated herpesviruses.
If the correlation between infection with these different infectious agents and an increased risk of subsequent dementia represents a causal relationship, then one would expect that immunization against or treatment of these infections would be correlated with a decreased risk of subsequent dementia. Several possible examples of such evidence are discussed elsewhere.
Read the full article: Yeh 2024