# Imaging the alpha7 nicotinic acetylcholine receptor in mild cognitive impairment

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $767,806

## Abstract

PROJECT SUMMARY
This project will assess the availability of the cerebral α7 nicotinic acetylcholine receptor (α7-nAChR) as a
contributing factor in the early pathophysiology of Alzheimer's disease (AD). Converging data suggest that the
α7-nAChR promotes accumulation of Aβ42 in cholinergic neurons, particularly in basal forebrain and
neocortical regions where the α7-nAChR is more highly expressed. High cerebral α7-nAChR availability (as
we have observed in normal aging), promotes intracellular sequestration of Aβ42 in cholinergic cells, and the
Aβ42-α7-nAChR interaction functionally antagonizes the α7-nAChR, which may be linked to progressive,
localized cell-death, synaptic loss, and aberrant neuronal activity long before spread of extracellular amyloid
plaque. The Aβ42-α7-nAChR complex drives upregulated expression of the α7-nAChR, fueling its further
interactions with soluble Aβ42 species. Based on published evidence and our preliminary data, we
hypothesize that higher, cerebral α7-nAChR binding will be observed in patients with MCI, the prodrome to
AD, compared to cognitively normal elderly controls using [18F]ASEM (ASEM) with positron emission
tomography (PET). We further hypothesize that higher availability of α7-nAChR in targeted brain regions will
be associated with 1. lower cognitive performance and 2. higher circulating, AD-relevant, biofluid biomarkers
such as α7-nAChR autoantibodies within these participants. We will thus test for hypothesized high
availability of the α7-nAChR in MCI compared to cognitively normal individuals, and its relationship to
cognitive performance (Aim 1), as well as its correlation with targeted biofluid markers that include plasma α7-
nAChR autoantibodies (Aim 2). Finally, in Aim 3, we will evaluate changes in α7-nAChR availability using
ASEM PET and its relationship to cognitive performance and these biofluid markers between baseline and
two-year follow-up in a subset of participants from Aims 1 and 2. The goal of this proposal is to test for high
brain availability of the α7-nAChR in MCI and its relationship to cognition and circulating AD-relevant
biomarkers - a critical step toward evaluating the α7-nAChR as an AD imaging biomarker with diagnostic and
therapeutic implications.

## Key facts

- **NIH application ID:** 10356804
- **Project number:** 5R01AG065202-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Arnold Bakker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $767,806
- **Award type:** 5
- **Project period:** 2020-02-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356804

## Citation

> US National Institutes of Health, RePORTER application 10356804, Imaging the alpha7 nicotinic acetylcholine receptor in mild cognitive impairment (5R01AG065202-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10356804. Licensed CC0.

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