# Immunoglobulin Genes and Immunity to HSV1 in Alzheimer's Disease

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $377,500

## 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. 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 ma...

## Key facts

- **NIH application ID:** 10896141
- **Project number:** 5R01AG080451-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** JANARDAN P PANDEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $377,500
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896141

## Citation

> US National Institutes of Health, RePORTER application 10896141, Immunoglobulin Genes and Immunity to HSV1 in Alzheimer's Disease (5R01AG080451-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10896141. Licensed CC0.

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