Human leukocyte antigen as a key factor in preventing dementia and associated apolipoprotein E4 risk

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Itzhaki's (2018) recent review discusses the evidence for a role of herpes virus (mainly herpes virus 1) in the development of Alzheimer's disease (AD), particularly among genetically vulnerable individuals. Specifically, the viral concept proposes that latent herpes virus in the brain of apolipoprotein E4 (apoE4) carriers is intermittently reactivated causing cumulative damage that ultimately results in AD. The viral concept and collective findings are particularly intriguing given the potential for intervention for AD aimed at neutralizing or eliminating herpes virus. Here we discuss human leukocyte antigen (HLA) as an additional genetic link in the viral concept of AD that not only accounts for the role of herpes virus in AD, but also extends to other viruses that may contribute to AD and to other diseases, and is consistent with beneficial brain effects of treatments aimed at eliminating the damaging effects of herpes virus via antivirals or IVIG as discussed in the review. Human leukocyte antigen (HLA) genes play a critical role in immune protection from foreign antigens including viruses, bacteria, and parasites (Meuer et al., 1982). HLA genes, which are the most highly polymorphic in the human genome, orchestrate production of cell-surface glycoproteins that facilitate immune surveillance and initiate an immune response to eliminate cytosolic or extracellular foreign antigens through cell destruction or antibody production. Recent studies have implicated the HLA region in neurodegenerative diseases including AD (Lambert et al., 2013; Steele et al., 2017); however, the concept of HLA-disease associations runs counter to the biological and evolutionary role of HLA which is to protect against invaders and promote species survival. Indeed, the literature is replete with studies highlighting the protective role of HLA in various conditions. For example, HLA-DRB1*13:02 has been shown to confer protection against various illnesses ranging from hepatitis B and C (Singh et al., 2007), influenza (Posteraro et al., 2014), HIV (Pereyra et al., 2010), malaria (Hill et al., 1991), and numerous autoimmune disorders (Bettencourt et al., 2015). Perhaps the most relevant in this case is recent evidence of HLA-protection against structural and functional age-related brain changes (James et al., 2018a,b). Notably, DRB1*13:02, has been shown to not only protect against age-related deterioration in neural network functioning, but also to negate the deleterious effects of apoE4 on neural network functioning (James et al., 2018b; Figure 1, top), suggesting a common pathway.

Original languageEnglish (US)
Article number82
JournalFrontiers in Aging Neuroscience
Issue numberAPR
StatePublished - 2019

Bibliographical note

Funding Information:
Partial funding was provided by the University of Minnesota (the Kunin Professorship for Women’s Healthy Brain Aging). The sponsors had no role in the current study design, analysis or interpretation, or in the writing of this paper. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Publisher Copyright:
Copyright © 2019 James and Georgopoulos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


  • Alzheimer's disease
  • Apolipoprotein E cognition
  • Brain
  • Herpes virus
  • Human leukocyte antigen (HLA)


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