# Immunoglobulin GM (γ marker) Allotypes and Immunity to HSV1 in Alzheimer’s Disease

> **NIH NIH R56** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $366,990

## Abstract

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.
Clearly, 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 biotinylated HSV-gD as target, we will determine
whether the level of ADCP is associated with particular combinations of Fcg (GM) and FcgRIIa alleles. Results
of this investigation may...

## Key facts

- **NIH application ID:** 10464940
- **Project number:** 1R56AG073670-01
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** JANARDAN P PANDEY
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,990
- **Award type:** 1
- **Project period:** 2021-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464940

## Citation

> US National Institutes of Health, RePORTER application 10464940, Immunoglobulin GM (γ marker) Allotypes and Immunity to HSV1 in Alzheimer’s Disease (1R56AG073670-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10464940. Licensed CC0.

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