Linking olfactory deficits to memory impairment and AD neurodegeneration

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ABSTRACT Olfactory impairment may signal prodromal Alzheimer’s disease (AD). We currently do not have an established model that can be tested, in vivo, relating AD neurodegeneration to specific functional deficits in olfaction and memory. This significant knowledge gap impedes the development of functional imaging markers for the evaluation and diagnosis of AD. We have developed several olfactory fMRI paradigms that can probe the dysfunctions in brain regions where early stage AD neurodegeneration occurs. Our preliminary data suggest an AD neurodegeneration-to-function model. We hypothesize that progressive neurodegeneration in MCI disrupts the connectivity of the olfactory network (ON) to the default mode network (DMN) via the Hippocampus, leading to early deficits in olfaction followed by memory impairment. Our research is designed to test this hypothesized model using functional connectivity (FC; synchrony among brain regions) in resting state fMRI and effective connectivity (EC; directed interactions between brain regions) during olfactory task fMRI; neurodegeneration will be evaluated by volumetric MRI (vMRI). Aim 1: Determine age-related changes in the ON-DMN network in cognitively normal subjects. Aim 2: Determine changes in the ON-DMN network in mild cognitively impaired (MCI) subjects. Aim 3: Explore the relationships between progressive changes in the ON-DMN network, and cognitive decline in MCI subjects The over-arching goal of the proposed research will be to rigorously test an AD neurodegeneration model that answers two fundamental questions: a) How are odor-identification and odor-discrimination deficits in AD related to memory impairment and neurodegeneration? and b) Do olfactory deficits and progressive disruptions to ON- DMN connectivity signal the development of AD dementia? Research outcomes can provide numerous avenues for improving olfactory testing as an AD marker. Olfactory tests, which target specific brain areas and processes that are affected earliest in AD, could hold additional promise for early disease detection and prevention in other neurodegerative disease, such as Parkinson’s disease.