# Investigating the role of long-term latent herpes simplex virus infection on APOE4-associated Alzheimer's disease pathogenesis

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $828,847

## Abstract

Project Summary
47 million people worldwide are living with Alzheimer's disease (AD) or a related form of dementia. In the US
alone, the annual health care costs for people with AD will exceed 1 trillion dollars by 2050. However, current
treatments do not robustly prevent disease progression. The major risk factors for the late-onset form of AD are
advanced age and possession of the ε4 allele of apolipoprotein E (APOE). Importantly, increasing data support
the hypothesis that latent herpes simplex virus 1 (HSV-1) infection is also a risk factor, especially in combination
with the APOE4 allele. This suggests that current antivirals may halt or delay neurodegenerative disease
progression in APOE4 carriers who are infected with HSV-1. A major gap in the study of this association,
however, is the absence of an HSV infection model reflecting the complexity of long-term latent infection,
particularly in the context of APOE4 and AD. In our preliminary studies, we observed that HSV-1-infected APOE4
mice, compared to mock-infected APOE4 mice and HSV-1-infected WT mice, displayed robust spatial memory
deficits, as well as oxidative stress, iron dysregulation, and gliosis in the CNS when assessed 15 months post
infection (mpi), but not at 3 mpi. The objective of this proposal is to use this model, as well as complementary in
vitro models, to fully elucidate the effects of long-term latent HSV-1 infection, in the context of differential APOE
isoform expression, on brain function and AD pathogenesis. We will also assess whether treatment with a novel,
brain-penetrant antiviral medication can block these effects. We anticipate that the full study proposed herein
will uncover unique and important interactions between HSV-1 infection and APOE genotype in driving AD
pathogenesis, potentially leading to safe and effective new therapeutic strategies for preventing or slowing AD
in at-risk individuals.

## Key facts

- **NIH application ID:** 10901915
- **Project number:** 5R01AG083963-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Anna Ruth Cliffe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $828,847
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901915

## Citation

> US National Institutes of Health, RePORTER application 10901915, Investigating the role of long-term latent herpes simplex virus infection on APOE4-associated Alzheimer's disease pathogenesis (5R01AG083963-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10901915. Licensed CC0.

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