The overall goal of this project is to identify patterns of abnormal brain function that characterize mixed neurodegenerative pathologies. Traditional models of neurodegenerative disease (ND), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), assume that a specific protein abnormality triggers a cascade of changes that lead to neuronal damage and eventually to a characteristic pattern of abnormal brain function. Yet, autopsy studies on ND patients often reveal a mixture of pathologies, involving several putative disease-specific proteins. Determining whether a patient suffers from an ND that is governed by a specific abnormal protein or affected by multiple others has different implications for clinical care, especially for protein targeting therapies - once they become available. This project will relate variations in abnormal brain function as measured using functional magnetic resonance imaging (fMRI) to variations in abnormal protein levels in cerebrospinal fluid (CSF). A novel approach for analyzing fMRI data is used that quantifies the complexity as well as the unpredictability of the fMRI signal. The specific aims of the project are twofold: First, the hypothesis will be tested that interactions among abnormal CSF proteins lead to less complexity of brain function and greater unpredictable, suggesting that multiple abnormal proteins contribute to ND. Second, the degree to which reduced complexity and increased unpredictability are potential markers for mixed ND pathology will be tested. It is expected that feasibility to detect mixed ND pathologies by fMRI, which is safer and cheaper than other imaging methods, can be demonstrated. The detection of mixed ND pathologies is important for optimizing patient health care, homogenizing cohorts in clinical trials, and informing development of novel protein targeting therapies.