VIRAL INFECTION AND COGNITIVE DECLINE

Abstract

To the Editor: We were interested to read the paper by Aiello et al.1 on cytomegalovirus (CMV) antibody levels and cognitive decline. It fits well—as the authors point out—with our data suggesting that herpes simplex virus type 1 (HSV1) deoxyribonucleic acid (DNA) in the brain of apolipoprotein E ɛ4 carriers is a strong risk factor for Alzheimer's disease (AD)2, 3 and with our recent finding that the virus acts by causing formation of amyloid plaques and of abnormally phosphorylated tau (unpublished data). Specifically, the results of Aiello et al. are consistent with our hypothesis that events such as stress, immunosuppression, and inflammation caused by entry of cytokines into the brain after systemic infection can reactivate the virus, which we found to be present in a high proportion of elderly brains, normally in a latent state.4 (This parallels the situation in the peripheral nervous system, where it is known that stress, immunosuppression, etc. cause reactivation of latent HSV1 and that reactivation, in some people, causes orofacial lesions (cold sores).) Perhaps chronic, systemic, latent CMV infection—as proposed by Aiello et al.1—also causes cytokine entry into the brain, and indeed the authors suggest that high levels of CMV immunoglobulin G (IgG) antibody lead to rising levels of peripheral cytokines. Our hypothesis proposes further that, in view of the known inflammatory effects of viruses, the acute infection of the brain resulting from reactivation of HSV1 augments the cytokine-induced inflammation, leading to cognitive decline. Studies in mice with preclinical prion disease, which show that, after injection with lipopolysaccharide, the animals suffer more inflammation than uninfected controls, indirectly support the hypothesis that such augmentation takes place.5 Aiello et al.1 comment that most studies report no association between presence of HSV1 DNA in the brain and dementia. To clarify this point, we would add that, in the case of most or all infectious agents, presence of the agent does not necessarily lead to disease; it is genetic factors that determine the outcome and severity of infection6, 7 (e.g., Mycobacterium tuberculosis infects 10 times as many people as those who develop tuberculosis, and HSV1 infects (in the peripheral nervous system) four times as many people compared with those who develop cold sores). In the case of AD, the genetic factor implicated with HSV1 is apolipoprotein E ɛ4. A further point relating to this virus, which might relate also to the authors' investigation of levels of HSV1-specific IgG in serum, is that Vestey et al.8 showed that the titer remained unaltered through several orofacial recrudescences and during the time between. Financial Disclosure: None. Authors Contributions: Both authors prepared the letter. Sponsor's Role: None.