Comment on "cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals," journal of infectious diseases, 8 august 2014.

TO THE EDITOR—Barnes et al [1], in their interesting article on herpes viruses and Alzheimer’s disease (AD), conclude that human cytomegalovirus (hCMV), but not herpes simplex virus type 1 (HSV-1), is involved in causation of AD. This is based on the authors’ finding a greater proportion of elderly people with serum antibodies to hCMV than to HSV-1. However, if we examine the methodology that Barnes et al [1] used to determine antibody to HSV-1 and compare it with the methodology used to determine antibody to hCMV, it is immediately apparent that serologically, like is not being compared with like. Herpesviruses produce a wide variety of proteins and precursors of these proteins during their replicative cycle. A total of 77 open reading frames have been identified in the genome of HSV-1, of which the product of just 1—glycoprotein g—is used in type-specific serological assays used to define an HSV-1 immune response. In contrast, the larger genome of hCMV has between 165 and 252 open reading frames, and serological assays for hCMV antibody typically utilize the full complement of hCMV proteins and their precursors (prepared from a lysate of human embryo lung fibroblast cells infected with hCMV). Thus, if one wishes to compare serological evidence of past exposure to HSV with serological evidence of past exposure to hCMV, assays of equivalent sensitivity need to be used. The use of a type-specific assay for HSV-1 is particularly problematic in elderly populations with waning immune responsiveness. As the authors point out, there is a paucity of data on HSV-1–specific seroprevalence in the elderly. Nonetheless, their seroprevalence for HSV-1 of only 44% is surprisingly low, and at odds with the value of 80% found in other US studies (eg, [2]). The authors also stated that “the relationships [of antibodies] were independent of HSV-1 status, Viruses and AD which showed no relationship with risk of AD or cognitive decline. ” Their data contrast with those of many studies seeking microbial serum antibodies in AD patients, and also with data on serum antibodies and cognitive decline. The studies on AD examined antibodies to HSV-1 and, in some cases, also to hCMV and to certain bacteria [3], and all the results implicated specifically HSV-1 and, in some cases, its reactivation in the brain, to the risk of AD. In the case of cognitive decline, the study by Barnes et al [1]contrasts with others relating the decline in older age to HSV-1 [3]; for example, Tarter et al [4] state: “Among older adults, HSV-1 seropositivity was associated with immediate memory impairment”; and Prasad et al [5] state: “Cross-sectional studies have also identified an association between HSV1 exposure and lesser degrees of cognitive impairment among healthy control individuals and patients with bipolar disorder . suggesting etiological links between HSV1 exposure and cognitive impairment. Exposure to other human herpes viruses such as cytomegalovirus and herpes simplex virus type 2 may also be associated with cognitive impairment, but the data are less consistent. ” In a recent letter to this Journal we commented on another study, by Lurain et al [6], which seemingly implicated CMV in AD; in fact, these results are fully explained by the suggestion of Stowe et al [7] that CMV can influence immune response to other pathogens, and might trigger the immune dysregulation involved in some age-related diseases, and specifically, that HSV-1 reactivation is associated with CMV and age. In their discussion, the authors assert that “some studies have found that HSV1 is related to AD but the results have been inconsistent . ” In fact, there are over 80 publications by various groups that directly or indirectly support the concept that HSV-1 is a cause of AD, but only 2—published 11 and 13 years ago—that oppose it.