Imaging the alpha7 nicotinic acetylcholine receptor in mild cognitive impairment

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.

Grant Number: 5R01AG065202-05
NIH Institute/Center: NIH
Principal Investigator: Arnold Bakker