| Summary: | Repeated reactivations of latent herpes simplex virus type-1 (HSV-1) in the central nervous system (CNS) may contribute to neurodegeneration in Alzheimer’s disease (AD) patients. Immune response is a key element for the control of viral reactivation. HSV-1 uses a number of strategies to evade immune recognition, Immunoglobulin G 3 (IgG<sub>3</sub>) alone counteracts humoral immunoevasion, as it is the only IgG subclass that is not blocked by the HSV-1 Fc receptor, a protein that protects virion and infected cells from antibody-mediated effector mechanisms. We examined HSV-1-specific IgG<sub>3</sub> titers in serum of AD (<i>n</i> = 70) and mild cognitive impairment (MCI) (<i>n</i> = 61) subjects comparing the results to those of 67 age- and sex-matched healthy controls (HC); associations between MRI-determined brain cortical health and HSV-1-specific IgG<sub>3</sub> were analyzed in a subgroup of AD and MCI subjects. HSV-1-specific IgG<sub>3</sub> were more frequently detected in MCI compared to AD and HC subjects. Significant inverse correlations were found between IgG<sub>3</sub> titers and brain cortical thickness in areas typically involved in dementia and HSV-1 encephalitis in AD patients; interestingly, this negative correlation was much less important in MCI subjects. All together these results suggest that in AD an inefficient IgG<sub>3</sub> humoral immune response, failing to block viral replication, contributes to progressive neurodegeneration.
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