# Pathogenic exosomes during herpes zoster mediate increased vascular dementia risk

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $651,387

## Abstract

Project Summary: Vascular dementia is the second most common cause of dementia. Therapies aim to
control risk factors (e.g. hypertension, hyperlipidemia, and diabetes mellitus) to prevent development or
worsening of disease. Recent studies show that viral infections are potentially modifiable risk factors for
dementia. Amongst all pathogens, varicella zoster virus (VZV) is the most likely contributor to vascular
dementia. VZV is a neurotropic DNA virus that is latent in >95% of Americans and reactivates to produce
herpes zoster (shingles) in 50% by 85 years of age. Despite the availability of zoster vaccines, there are still >1
mil cases of zoster annually. Recent studies reveal zoster increases dementia risk and treatment (vaccines,
antivirals) reduces risk. Importantly, a recent FinnGen and U.K. biobank study showed VZV was specifically
associated with an increased risk of vascular dementia. VZV likely contributes to vascular dementia risk
through its well-established ability to produce vascular pathology leading to ischemic or hemorrhagic stroke
(VZV vasculopathy). VZV directly infects cerebral arteries and causes a vasculitis, as well as induces a
prothrombotic state triggering cerebral thrombosis. A notable feature is the involvement of soluble factors that
promote vasculitis or thrombosis distal from the site of rash. We recently showed that plasma exosomes
isolated from acute zoster patients contained significantly elevated prothrombotic and proinflammatory proteins
including thrombospondin-1, caveolae-associated protein 2, coagulation factors V and XIIIA1, calmodulin 1,
and transthyretin compared to matched controls. These exosomes were non-infectious but induced IL-6 and
IL-8 secretion when applied to naïve primary human brain vascular adventitial fibroblasts, activated donor
platelets, and induced platelet-leukocyte aggregations supporting a proinflammatory and prothrombotic state.
Importantly, these exosomes persist for at least 3 months post-zoster, well after rash clearance and detectable
viremia. Overall, we hypothesize that circulating exosomes during zoster and in subsequent months will
promote vasculitis and thrombosis, thus providing a mechanistic basis for the increased vascular dysfunction
risk preceding vascular dementia. To test this hypothesis, we will isolate plasma exosomes from individuals
during acute zoster and at 7 days, 1 month, 3 months, 6 months, and 12 months post-zoster, as well as isolate
exosomes from matched control individuals during a single clinic visit. Aim 1 will analyze exosome content for
known vascular damaging proteins/miRNAs from matched control and zoster individuals over a 12-month
period. Aim 2 will determine the mechanism(s) in which non-infectious zoster exosomes promote vascular
dysfunction. Understanding how long-lasting pathogenic exosomes promote cerebrovascular disease during
and after zoster, thereby accelerating vascular dementia risk, is significant because it will potentially change
cli...

## Key facts

- **NIH application ID:** 10806533
- **Project number:** 1R01AG085406-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Andrew N Bubak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $651,387
- **Award type:** 1
- **Project period:** 2024-09-20 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806533

## Citation

> US National Institutes of Health, RePORTER application 10806533, Pathogenic exosomes during herpes zoster mediate increased vascular dementia risk (1R01AG085406-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10806533. Licensed CC0.

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