# Neurophysiological Basis for Functional Connectivity Changes in Early Alzheimer’s Disease

> **NIH NIH F30** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $48,040

## Abstract

Abstract
Early diagnosis and treatment of Alzheimer’s disease (AD) are critical for delaying the onset of clinical symptoms,
such as cognitive impairments and memory deficits. Early in AD, cognitively normal individuals who are positive
for amyloid-β, a predictive biomarker of AD, exhibit a transient increase in brain connectivity prior to a decline in
brain connectivity and cognition. This hyper-connectivity phase of AD suggests a prodromal pathology that may
be exploited as an early biomarker prior to the onset of clinical symptoms. Though these changes in brain
network connectivity have been well documented, little is known about the underlying neuropathology. I seek to
test whether localized increases in excitatory neuronal activity caused by amyloid-β drive the brain-wide hyper-
connectivity observed in early AD. I will use a multimodal imaging approach to determine the impact of amyloid-
β on neuronal and glutamate activity on the scale of the neuron (microscopic), regional neuronal circuit
(mesoscopic), and inter-regional network connectivity (macroscopic) in mouse models of AD. My proposal
comprises the following three aims: Aim 1: Determine the impact of acute exposure of amyloid-β on neuronal,
glutamate, and network activity in the normal cortex, Aim 2: Determine the impact of chronic, progressive
amyloid-β accumulation on neuronal, glutamate, and network activity in a young mouse model of AD, and Aim
3: Determine how total glutamate concentration changes, measured by translational magnetic resonance
spectroscopy, relate to synaptic glutamate activity changes with disease progression. Together, these
experiments could determine the neurophysiological underpinnings of the connectivity changes observed in early
AD. Data from this study could introduce novel treatment strategies for patients at risk of developing AD.
Furthermore, this work closely integrates my clinical interest in neuroimaging and neurology. In addition to
rigorous mentored research training, this proposal includes clinical experience and professional development
that will facilitate my growth into an independent physician-scientist.

## Key facts

- **NIH application ID:** 10534529
- **Project number:** 1F30AG079507-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Christopher Gregory Cover
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $48,040
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534529

## Citation

> US National Institutes of Health, RePORTER application 10534529, Neurophysiological Basis for Functional Connectivity Changes in Early Alzheimer’s Disease (1F30AG079507-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10534529. Licensed CC0.

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