# Cholinergic Receptors in Aging and Early Alzheimer's Disease: Longitudinal Change

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2021 · —

## Abstract

Cholinergic receptors in aging and early Alzheimer’s disease: longitudinal change
David Sultzer, MD
VA Greater Los Angeles Healthcare System
Abstract
The overall goal of this study is to evaluate the role of the brain cholinergic neurotransmitter system in
cognitive aging and the progression to Alzheimer’s disease (AD). The study examines changes in nicotinic
cholinergic receptor binding over time among healthy older Veterans and those with mild cognitive impairment
(MCI) and measures the association between receptor binding change and clinical cognitive change.
Memory decline with aging and AD are now critical healthcare challenges as the Veteran population ages.
While several neurobiological factors contribute to cognitive aging and the neurodegenerative cascade of AD,
their individual and interactive roles are poorly understood, the involvement of neurotransmitter systems has
not been well-studied, and efficacious targeted treatments have been elusive.
The cholinergic neurotransmitter system has been shown to play a key role in the cognitive changes
associated with aging and AD. Recently, our group has used a novel PET imaging ligand, 2-18F-fluoro-3-
(2(S)azetidylmethoxy) pyridine (2FA) to measure nicotinic cholinergic receptor binding in vivo in healthy older
adults and those with MCI and AD. Results indicate that binding is modestly reduced regionally in MCI and
more extensively reduced in mild and moderate AD. In the healthy and MCI groups, 2FA binding is inversely
associated with age and cognitive deficits. Reduced binding is not solely a reflection of hippocampal atrophy in
a preliminary analysis. The emerging model postulates that nicotinic receptor binding dysfunction is a primary
event in aging and early AD neurodegeneration. This receptor dysfunction alters downstream neurotransmitter
release, synaptic plasticity in key structures, and function across neural systems, with distinct clinical
consequences.
The proposed project takes the next step to evaluate longitudinal change in the nicotinic cholinergic system:
Healthy older Veterans and those with MCI undergo 2FA PET imaging and cognitive assessment, with repeat
assessments at least two years later. Change in regional nicotinic cholinergic receptor binding will be
measured and relationships between binding changes and changes in memory, attention, and global cognition
will be assessed. The relative contribution of atrophy in two structures related to acetylcholine availability and
post-receptor translational effects, the basal forebrain and hippocampus, are also explored. In addition,
participants undergo FDG-PET imaging to measure metabolic activity in cortical regions known to be affected
by AD. Thus, the decline in nicotinic cholinergic receptor binding, associations with cognitive changes, and the
influence of basal forebrain and hippocampal atrophy can be assessed in the context of a likely AD
neurodegenerative process.
Results from this study can better define the role of regio...

## Key facts

- **NIH application ID:** 9892958
- **Project number:** 5I01CX000409-07
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** REBECCA J MELROSE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892958

## Citation

> US National Institutes of Health, RePORTER application 9892958, Cholinergic Receptors in Aging and Early Alzheimer's Disease: Longitudinal Change (5I01CX000409-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9892958. Licensed CC0.

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