Early Detection of Prodromal Brain Network Activity in Alzheimer’s Disease

About This Grant

Project Summary / Abstract Prodromal symptoms of AD occur years or even decades before the onset of cognitive symptoms in Alzheimer’s disease and may serve as an early diagnostic tool in identifying individuals at risk for dementia. However, since these symptoms are non-specific, they are often missed or attributed to other health-related issues, and even when they are noticed it can be difficult to make a clear determination of AD risk. The goal of the present application is to identify a neural signature that can clearly distinguish between early AD and normal aging. In Aim 1, we will record from 10 brain regions that have been implicated in behavioral process that are disrupted in prodromal AD in mouse model of human tauopathy (htau mice) and wild-type controls (C57BL/6J) across the lifespan. Htau mice display behavioral deficits reminiscent of prodromal AD as well as reductions in 5-HT expression and neural activity starting at 4 months of age, so we expect network-level disruptions at that timepoint or earlier. Here in Aim 1 we will compute new electrical oscillatory features (Electome factors) that distinguish htau and C57BL/6J mice at different ages. As a converging approach, we will also assess predetermined Electome factors in these mice that were previously defined in mouse models of stress vulnerability. The translational potential of the model will be enhanced by leveraging Electome factor activity to identify specific network features in resting state fMRI that define prodromal AD across the aging spectrum. Once we have defined a neural signature of early AD, Aim 2 will assess the role of brainstem monoaminergic neurons in driving these network-level changes in the brain. Serotonergic and noradrenergic neurons in the DRN and LC accumulate tau pathology prior to the entorhinal cortex, leading to neurodegeneration. These neurons also have well-delineated roles in sleep, mood and arousal which are disrupted in prodromal AD. In Aim 2, we will use 3D imaging as well as genetic and chemogenetic manipulations in Sert-cre x htau and Dbh-cre x htau mice to determine whether monoaminergic depletion or reduced neuronal activity drives network activity in early AD.