# Manipulating neural oscillations with non-invasive sensory stimulation for Alzheimer's disease intervention

> **NIH NIH R56** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $761,748

## Abstract

Alzheimer's disease (AD) is a debilitating brain disorder, with staggering human and financial cost in a rising
aging population, and the complexity of the disease's underlying pathophysiology presents a major challenge in
developing therapeutics. Recently, in an approach that we term Gamma ENtrainment Using Sensory stimuli
(GENUS), we found that neural oscillations in the gamma frequency range (30-90 Hz) could be induced to impact
pathology in AD mouse models by exposing them to flickering light at 40 Hz or 40 Hz train of auditory pure tone.
We found that GENUS reduces amyloid burden and hyperphosphorylated tau in respective amyloid and
tauopathy mouse models, as well as modifies microglia, astrocytes and vasculature. We also show that
multimodal GENUS can be applied with simultaneous auditory and visual stimulation, and prolonged visual
GENUS promises longer-lasting effects. Further, we report reduced AD pathology not only in the primary sensory
cortex but also in the hippocampus and medial prefrontal cortex. Thus, the goal of our proposed research is
to determine the efficacy and durability of multimodal GENUS and whether the beneficial effects of
multimodal GENUS can be modulated by AD-related drug treatments and AD-risk carrier of APOE. To
this end, we will systematically characterize the temporal profile of chronic multimodal GENUS (1 or 2 h/day)
and determine the decay time of post-GENUS in amyloid and tau mouse models. We hypothesize that chronic
multimodal GENUS for 6 weeks may impact different brain areas for longer periods. We will assess whether
FDA approved drugs could modulate and enhance the longer-lasting decay time of post-GENUS after 6 weeks
of multimodal GENUS. We will test an acetylcholinesterase inhibitor, an NMDA receptor antagonist, and an
antiepileptic drug combined with chronic multimodal GENUS. APOE4 is the highest risk gene for sporadic AD,
and ~40% of the global AD population carries at least one copy of APOE4. As such, we will investigate how
APOE4 modifies GENUS response. Our recent studies show that GENUS impacts neurons, microglia, astrocytes
and the vasculature, all of which are associated with APOE. We will use humanized APOE-knock in mice and
APOE-knock in mice crossed with amyloid and tauopathy mouse models to determine whether APOE can modify
the response to GENUS.

## Key facts

- **NIH application ID:** 10228379
- **Project number:** 1R56AG069232-01
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Li-Huei Tsai
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $761,748
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228379

## Citation

> US National Institutes of Health, RePORTER application 10228379, Manipulating neural oscillations with non-invasive sensory stimulation for Alzheimer's disease intervention (1R56AG069232-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10228379. Licensed CC0.

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