PROJECT SUMMARY Alzheimer's disease (AD) is a neurodegenerative disease resulting in dementia and ultimately, death. No cure exists for the disease and treatments start only after symptoms are presented. Thus, early AD detection is crucial to start the treatment to slow down the progress of the disease. Olfactory dysfunction is shown to be present as a disturbed sense of smell, proposed as an early sign of neurodegenerative diseases, but also including AD. The mechanisms underlying olfactory deficits in AD remain largely unknown. Olfactory bulb (OB) and its associated piriform cortex (PCX), a region that is involved in olfactory learning, can be a key candidate for investigating early functional changes in the brain induced by AD pathology. In addition, functional and structural changes in entorhinal cortex (EC) and hippocampus (HC) can be detected years before significant clinical symptoms, and therefore, suggested as potential biomarkers for AD diagnosis. There are a close anatomical and functional associations between olfaction (OB-PCX) and memory (EC-HC) systems. OB-PCX circuit is closely connected with the EC-HC circuit and is suggested as one of the earliest regions affected by AD. Therefore, we hypothesize that progressive neurodegeneration in AD disrupts the connectivity of the olfactory circuit to the memory circuit, leading to early deficits in olfaction followed by memory impairment. Detection of structural, functional and behavioral changes related to olfactory and memory function may result in early AD detection. Our recent work to study AD progression in a rodent model and its response to therapeutic intervention serves as the basis, as well as our recent innovation in a novel functional MRI (fMRI) method which enables simultaneous imaging of the rat cerebral cortex and the olfactory bulb. The overall goal of this project is to develop neuroimaging methodologies that enable early detection of AD and olfactory function via biomarker imaging. To achieve this goal, we will longitudinally perform imaging/spectroscopic and behavioral studies on transgenic TgF344-AD and wildtype (WT) rats from early to more advanced stages of the disease (3-12 months) (Aim 1) and assess mitochondrial energy metabolism (Aim 2). We will use in vivo multi-modal MRI/MRS (at 11.7T) in conjunction with behavioral testing to characterize AD development and progression. We will specifically examine the (a) functional connectivity alterations in the olfactory networks using resting fMRI and bulbar/cortical responses by task fMRI, (b) mitochondrial energy metabolism by 31P-MRS and (c) memory and smell abilities using behavioral measurements (novel object recognition, spatial memory and olfactory tests). The characterization of AD pathology in this rat model using highly translational MRI techniques highlights the potential of this model to be used in valuable future preclinical AD research as well as its use for potential treatment evaluation.