The Association Between Herpes Simplex Virus and Alzheimer’s Disease: A Systematic Review

October 2023 | Volume 22 | Issue 10 | 1046 | Copyright © October 2023


Published online September 30, 2023

doi:10.36849/JDD.6785

Marc Cohen BSa, Evan Austin BSa, Stefan Bradu MD PhDa,b, Jared Jagdeo MD MSa,b

aDepartment of Dermatology, State University of New York, Downstate Medical Center, Brooklyn, NY
bDermatology Service, VA New York Harbor Healthcare System Brooklyn Campus, Brooklyn, NY

Abstract
Alzheimer's disease (AD) is a significant public health concern, affecting more than 6 million Americans; and currently, there are no cure or effective treatment options. The underlying etiology and pathogenesis are not fully understood, presenting a barrier to therapy. A substantial amount of data exists associating infection with Herpes simplex virus 1 (HSV-1) and AD. This review of published studies highlights the epidemiological associations between HSV-1 and AD. A systematic search of PubMed, Embase, and Web of Science was conducted on January 6, 2022, using PRISMA guidelines. Articles that presented epidemiological data correlating HSV-1 with AD were included. Bibliographies were screened for additional relevant articles as well. After review, 21 studies were included: 2 review articles and 19 population-based studies including case control, cohort, and cross-sectional studies. 

The quantitative data derived from the studies in this report substantiate a relationship between infection with HSV-1 and AD. Based on these results, it may be of reasonable benefit to more consistently treat latent or active HSV-1 infection with anti-viral medications to potentially reduce the risk of AD. Furthermore, a prospective randomized controlled clinical trial could elucidate the benefit of anti-viral therapy to prevent or limit AD.

J Drugs Dermatol. 2023;22(10):1046-1052     doi:10.36849/JDD.6785

INTRODUCTION

The underlying cause of Alzheimer's disease (AD), a progressive neurologic disorder that is the most common cause of dementia, is poorly understood. At present, the treatments currently available have limited or questionable benefits and no known preventative treatments exist.1 6.5 million Americans over 65 have AD and that number is expected to double by 2050. In 2021, 239 billion dollars a year was spent by Medicare on dementia and AD, a figure that represents 67% of total Medicare spending.2  The National Institutes of Health (NIH) spends approximately 3 billion dollars every year on AD research.3 The new drug Aduhelm, conditionally approved by the US Food and Drug Agency (FDA) in June 2021, has been met with controversy due to equivocal data regarding its efficacy, significant side effects, and high cost of treatment.4 Therefore, it may be of benefit to search for therapeutics to treat or prevent AD.   

Herpesviridae is a class of viruses that are common causes of mucocutaneous pathologies.5 The lesions caused by them are often benign and self-resolving and, therefore, immediate treatment is often not requested. Specifically, Herpes simplex virus 1 (HSV-1) can lead to commonly seen lesions around the oral mucosa and is often left untreated; however, anti-virals such as acyclovir and valacyclovir are frequently administered to manage more severe, acute infections or frequent outbreaks.5-7 

The neurotropic nature of HSV-1, as well as its ability to establish dormancy in the sensory root ganglia of the trigeminal nerve, has made it a target of research as a potential infectious etiology for AD.6 Various pathophysiologic mechanisms centering around neuroinflammation evoked by the virus in genetically susceptible individuals have been proposed.8 Recent studies demonstrate a strong correlation between HSV-1 and AD; however, treatment of HSV-1 for prevention of AD is not currently the standard of care. Due to the high prevalence of HSV-1 in the adult population, focusing on HSV-1 anti-viral suppression may be a reasonable course of action considering the possible link to AD in this cohort.9,10 

This review includes a literature search investigating epidemiological associations between AD and infection with Herpesviridae, most notably HSV-1, and reports findings and limitations of the reviewed articles. The included studies take the form of population-based studies of humans. Also, we discuss commonly described pathophysiological mechanisms proposed for this association as well as the clinical relevance for dermatologists. Dermatologists have an important role in AD prevention. Lastly, we believe that, based on the quality of existing evidence, it may be reasonable to treat HSV-1 infections using anti-virals to prevent future development of AD.