# Treating hyperexcitability in Alzheimer’s disease with levetiracetam to improve brain function and cognition

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $584,852

## Abstract

ABSTRACT
Alzheimer's Disease (AD) is the leading common cause of dementia, the leading cause of disability in older
persons, and the most expensive disease in the United States, with total costs over $200 billion per year.
Unfortunately, therapeutic options are limited, and new treatment targets are necessary. Recent work in both
human patients and animal models has suggested that cortical network hyperexcitability is a fundamental
element of disease pathophysiology, leads to the development of epileptiform activity, and plays a key role in
disease progression. It has been hypothesized that treatment of cortical hyperexcitability with anti-seizure
medications such as levetiracetam (LEV) may improve cognitive function and slow disease progression in AD.
Preliminary studies in patients have shown that LEV improves some measures of brain network function. In
this study, we propose a randomized, placebo-controlled crossover study evaluating the effects of 4 weeks of
low-dose versus high-dose LEV in improving cortical hyperexcitability, brain network function and cognition in
patients with mild AD. Participants with AD will undergo baseline evaluation for epileptiform abnormalities with
a 24-hour video-EEG monitoring followed by a 256-channel dense array EEG. Before and after each
pharmacologic intervention, we will systematically evaluate brain network function and cortical excitability by
collecting resting-state EEG, structural MRI, Arterial spin-label perfusion MRI, resting-state functional
connectivity BOLD MRI, neuronavigated Transcranial Magnetic Stimulation (TMS) in combination with
simultaneous EEG and EMG, and cognitive function with the Neuropsychological Test Battery. To define
abnormalities in cortical excitability (TMS measures, ASL perfusion) and brain network function (EEG power
and coherence, default-mode MRI connectivity, TMS cortical plasticity) in AD. Similar measures will be
collected in demographically similar healthy subjects. We will determine the relationship between baseline
abnormalities in cortical excitability, brain network function, and cognitive performance; the effects of LEV
therapy on each of these measures; and identify predictors of the LEV dose-response. We will also examine
whether the cognitive effects of LEV are related to normalization of cortical hyperexcitability, and identify
biomarkers of improved cognition for use in other studies. Finally, we will determine whether the efficacy and
optimum dose of LEV are related to the presence of epileptiform abnormalities. This study will thus provide key
evidence for treatment of cortical hyperexcitability as a novel disease target in patients with AD, and provide
compelling mechanistic support for inclusion of LEV in the treatment armamentarium for AD.

## Key facts

- **NIH application ID:** 9869830
- **Project number:** 5R01AG060987-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Mouhsin Shafi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $584,852
- **Award type:** 5
- **Project period:** 2019-02-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869830

## Citation

> US National Institutes of Health, RePORTER application 9869830, Treating hyperexcitability in Alzheimer’s disease with levetiracetam to improve brain function and cognition (5R01AG060987-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869830. Licensed CC0.

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