Alzheimer’s disease (AD) is a heterogeneous and complex disorder and both genetic and environmental factors are likely to be involved in its etiology. Hundreds of putative susceptibility genes for late-onset AD have been reported, but the majority of these claims—with the exception of the e4 allele of the apolipoprotein E gene—have not been consistently replicated. Furthermore, the functional significance of the majority of the positional candidate genes in AD pathogenesis is not clear. One putative environmental (viral) factor that has been implicated in AD etiology is herpes simplex virus type 1 (HSV1). An infectious etiology for AD would suggest that the genes of the host immune system might also mediate the putative pathways towards the development of this disorder. Indeed, the genome-wide association studies (GWAS) and meta-analyses of AD have reported many risk-conferring genes that are enriched in the immune system pathways. The GWAS of AD, however, do not evaluate a major gene complex of the immune system—GM (g marker) allotypes encoded by immunoglobulin heavy chain G (IGHG) genes on chromosome 14. HSV1 is a ubiquitous herpesvirus. Not all HSV1-infected people are equally likely to develop AD-related complications, suggesting the involvement of host genetic factors in the HSV1-spurred dementia. Immunoglobulin GM allotypes are excellent candidate genes for modifying the HSV1-AD association, because they modulate the HSV1 immunoevasion strategies and, epistatically with Fcg receptor (FcgR) genes, contribute to the magnitude of antibody-dependent cellular cytotoxicity of HSV1-infected cells. In a recent study, we have shown that a GM genotype was associated with a 4-fold increased risk of AD. This association was independent of apolipoprotein e4 genotype and other AD risk genes. Based on these observations, we hypothesize that GM genes are risk factors for AD, and the underlying mechanisms include their influence on the magnitude of humoral immunity to HSV1 proteins and antibody-dependent cellular phagocytosis (ADCP) of neuronal cells. The following specific aims will test our hypothesis: 1) Determine if GM genotypes are risk factors for Alzheimer’s disease. DNA from a large study population of AD patients and controls will be characterized for several GM alleles to confirm our preliminary findings; 2) Determine if the magnitude of antibody responsiveness to particular HSV1 proteins is associated with GM alleles. We will quantitate antibody responses to HSV1-gD (a major glycoprotein and vaccine candidate) in the sera of AD patients and controls and determine if the magnitude of antibody responsiveness is associated with GM allotypes; 3) Determine if particular allelic combinations of Fc (GM) and cellular FcgR alleles influence the level of ADCP. Using HSV-gD as target, we will determine whether the level of anti-HSV1- gD-mediated ADCP is associated with particular combinations of Fcg (GM) and FcgRIIa alleles. Results of this investigation may begin to address the recurrent criticism of studies documenting the HSV1-AD association: Why the prevalence of HSV1 infection does not correlate with the prevalence of AD in the population?

PROJECT NARRATIVE: RELEVANCE About half the people aged 85 or over suffer from Alzheimer disease. Increasing evidence implicates herpes simplex virus type 1, a common herpesvirus, in this disease, and this project aims to investigate how certain genes influence immunity to this virus in patients with Alzheimer’s disease. Results of this investigation may help identify novel targets of immunotherapy against this disorder.