# Noninvasive Neurostimulation to Reduce Pathology in a Female Mouse Model of Alzheimer's Disease

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2023 · —

## Abstract

Over half a million U.S. veterans have Alzheimer’s disease (AD). With AD diagnoses increasing each
year, treatments are urgently needed. Despite this need, no clear effective treatment exists for AD and
interventions tested in nonhuman models often fail to translate to successful clinical trials. As women are more
likely to develop AD than men, AD treatments must address sex as determining factor when evaluating
treatments prior to clinical use. Optimized treatments that have the potential to reverse AD neuropathology and
mitigate cognitive impairment at prodromal stages, prior to neural degeneration and cell death, are required.
 Exposure to noninvasive audiovisual neurostimulation at 40Hz (gamma flicker) stimulates neural activity
in brain regions first affected by AD pathology that are important for learning and memory, including the
hippocampus (HPC) and prefrontal cortex (PFC). Gamma flicker recruits microglia, the primary immune cell of
the brain, in the HPC and visual cortex in male 5XFAD mouse models of amyloidosis, as well as cytokine
expression in WT male mice. Neurotransmitters like dopamine and norepinephrine modulate the activation,
proliferation, and cytokine release from immune cells. Further, AD pathology includes disrupted expression of
brain-derived neurotrophic factor (BDNF), an important trophic factor for learning and memory. These
neuromodulators are reduced as AD progresses, revealing potential therapeutic targets for treating neural
dysfunction and disease. Despite known sex differences in AD pathology, there is a knowledge gap on how
flicker noninvasively elicits changes in the immune response, neuromodulators, and cognition in females.
Preliminary data in female 5XFAD mouse models of aggressive amyloid accumulation in AD suggest that
different frequencies could be key to optimally tuning neurostimulation for each sex. Thus, the central goal of
this proposal is to test the hypothesis that specific frequencies of audiovisual flicker are optimal for altering the
neuroimmune response of microglia and neuromodulators in brain regions important for learning and memory
affected by neurodegenerative disease for each sex. Through the CDA2 proposed research, male and female
5XFAD mice will be exposed to chronic audiovisual flicker (1hr/ day for 7 days), then flicker’s effects on 1) the
spectrum of glia reactivity across stimulation frequencies, 2) trophic factors and neurotransmitters that alter glia
reactivity, cognition, and neuroplasticity, and 3) working memory performance, will be measured.
 The proposed research will take place over the proposed 5-year timeline of the CDA2 at the Center for
Visual and Neurocognitive Rehabilitation (CVNR) of the Atlanta VA. The resources available include the Atlanta
CVNR, Emory University’s Goizueta Alzheimer’s Disease Research Center, the Department of Biomedical
Engineering at Georgia Tech, and Emory’s Proteomics and Microscopy cores. The mentoring team and the
CVNR will support training i...

## Key facts

- **NIH application ID:** 10640335
- **Project number:** 1IK2RX004544-01
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Ashley Prichard
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10640335

## Citation

> US National Institutes of Health, RePORTER application 10640335, Noninvasive Neurostimulation to Reduce Pathology in a Female Mouse Model of Alzheimer's Disease (1IK2RX004544-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10640335. Licensed CC0.

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