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.