Epidemiological Evidence for Herpesvirus Infection to Increase the Risk of Alzheimer's Disease

There is much debate these days over the contribution of persistent infection (such as by herpesviruses) to the development of Alzheimer's disease. Not everyone with the evident risk factors, such as obesity, frailty, chronic inflammation, and so forth, progresses from mild cognitive impairment to full blown Alzheimer's disease. Why is this? The state of viral infection and the ability of any given aged immune system to contain that infection could be the variables needed to explain why Alzheimer's disease is only prevalent rather than universal. Despite the results presented in today's open access study, the epidemiological evidence to date is mixed and contradictory regarding a significant role for herpesviruses in Alzheimer's risk.

The infection-senescence hypothesis suggests that a burden of infection results in a raised pace of creation of senescent cells, particularly in the immune system, including the immune cell populations of the brain. Over time, this overwhelms the systems responsible for clearing senescent cells. When too many senescent cells accumulate, all actively secreting pro-inflammatory signals, they collectively produce a self-sustaining state of chronic inflammation. That unresolved inflammation disrupts normal tissue function in many ways - and Alzheimer's disease is known to have a strong inflammatory component.

An alternative view is that persistent infection ramps up the generation of amyloid-β, in its role as an antimicrobial peptide, a component of the innate immune system. The early, preclinical stages of Alzheimer's disease are characterized by a slow accumulation of misfolded amyloid-β in the brain, and the amyloid cascade hypothesis is the dominant explanation for why the disease occurs: in essence, amyloid-β aggregates cause enough dysfunction and inflammation to trigger the later pathologies of the condition. Why do some people accumulate more amyloid-β than others? Perhaps because they have a greater burden of persistent infection. But again, a conclusive weight of evidence for this viewpoint has yet to emerge.

Herpesvirus infections, antiviral treatment, and the risk of dementia - a registry-based cohort study in Sweden

There is growing evidence to support the link between herpes infections and Alzheimer's disease (AD). Targeting herpesviruses with specific antiviral agents could provide new AD treatment possibilities if a preventive effect is confirmed. Herpes simplex virus type 1 (HSV1) is the herpesvirus most strongly associated with AD. Several population-based cohort studies have demonstrated an increased risk of AD development for carriers of HSV1. Both in vivo and in vitro, inoculation with HSV1 among other pathogens causes AD-related changes with amyloid deposition.

Another neurotropic member of the Herpesviridae family implicated in dementia development is varicella zoster virus (VZV). Herpes zoster ophthalmicus is a subtype of the herpes zoster infection that affects the ophthalmic division of the trigeminal nerve. VZV infection of the central nervous system (CNS) has previously been linked to long-term cognitive decline. Recent data suggest that herpes zoster ophthalmicus and herpes zoster infection are associated with a 3.0- and 1.1-fold increased risk of dementia development. It has been hypothesized that in the event of herpes zoster ophthalmicus, the virus more frequently spreads to the brain, thereby explaining a stronger association with dementia development.

Previous findings have indicated a potential protective role of antiviral treatment against dementia development, and these results need to be corroborated in other large-scale cohorts. The aim of this study was to investigate whether specific antiviral treatment targeting herpesviruses and herpes infection with VZV and HSV, in absence of treatment, affects the risk of subsequent dementia in a large registry-based cohort in Sweden. The matched cohort study followed 265,172 subjects with herpes diagnoses and antiviral treatment, and the same number of controls.

Individuals with herpes diagnoses who did not receive antiviral treatment had higher incidence rates of dementia compared to their controls (12.9 and 10.2 per 1000 person-years, respectively). In contrast, herpes-diagnosed subjects who received antiviral treatment had lower incidence rates of dementia than their controls (8.5 and 9.4 per 1000 person-years, respectively). Last, the dementia incidence rates of antiviral users irrespective of diagnosis and their controls were 6.6 and 7.4 per 1000 person-years, respectively). Specific antiviral treatment targeting herpesviruses was associated with an 11% risk reduction of dementia. In contrast, having received a herpes diagnosis without antiviral treatment was associated with a 50% increased risk of dementia compared to controls. These results are in line with previous register-based studies indicating the potential protective role of antiviral treatment in dementia.

The control group in this study comprised both seropositive and seronegative individuals as the seropositivity status of the subjects is unknown, especially considering that approximately 70% of the population could be expected to carry HSV1 and more than 95% VZV. It is reasonable to assume that the controls probably have better immunological resilience to herpes infections with fewer episodes of symptomatic reactivations because they have not received a herpes diagnosis or been subjected to specialist medical care for this. Importantly, the herpes diagnoses primarily reflect symptomatic reactivation or primary infection with overt signs. Thus, the individuals with herpes diagnoses constitute a subgroup of those carrying the pathogen.

Comments

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.