PROJECT SUMMARY Alzheimer’s disease (AD) is the leading cause of dementia, with the number of cases estimated to rise to 13 million by 2050 in the US alone . While amyloid-beta (Aβ) and tau are known to be the key neuropathological hallmarks of the disease, imaging and postmortem studies highlight significant variability in disease severity and progression even in subjects with similar burdens of Aβ and tau accumulation. This uncertainty in the trajectory of disease progression results in substantial challenges for patients and their families in understanding disease prognosis, as well as the research community in understanding heterogeneity in the rate of Aβ and tau accumulation, cognitive decline and likelihood of progressing to dementia. Building upon prior work from our group and others, we will develop a prognostic score, termed the Tau Progression Index (TPI), a multi- component and multimodal measure that can predict tau accumulation, neurodegeneration, and cognitive/functional decline. Two components of the TPI are based on MRI measures of structural and functional connectivity that have been shown in recent reports to explain the rate and pattern of spread of tau pathology. The other two components are based on regional patterns and interactions between Aβ and tau accumulation in the early stages of AD. For instance, a recent report by our group highlights the importance of co-localized (overlapping) and non-co-localized accumulation of Aβ and tau in predicting conversion from cognitively normal to mild cognitive impairment (MCI) and/or AD. In this project, we will recruit 130 non-demented participants with evidence of Aβ and tau pathologies based on 18F-florbetaben and 18F-MK6240 PET scans from 10 ongoing NIH-funded studies with more than 1700 planned and 650+ existing enrollments. Our laboratory serves as a central neuroimaging processing hub for these 10 NIH studies, allowing us a unique opportunity to identify subjects with PET-confirmed evidence of AD pathology at no additional cost. These selected subjects will then undergo our advanced MRI acquisition protocol and processing pipeline to extract reliable subject-specific functional and structural connectivity. Subjects will also undergo detailed cognitive and clinical assessments. Subjects will be evaluated at baseline and at a 2.5-year follow-up visit, which will include Aβ and tau PET, our advanced MRI and clinical/cognitive assessment. By combining subject-specific structural and functional connectomes with the patterns of Aβ and tau accumulation, our developed TPI will give a single prognostic score for each individual. We aim to show that this score will predict the trajectory of tau spread and disease progression. By incorporating spatial/network-based patterns of tau deposition and brain connectomes into a prognostic tool for patient counseling and clinical trials, our TPI is an important step towards personalized medicine for AD.

Project Narrative The trajectory of Alzheimer’s disease progression is extremely heterogeneous, both spatially and temporally, which makes it challenging for patients and their families to plan for the future, for clinical research to target appropriate cohorts for clinical trials, and for scientists to investigate disease pathophysiology in a systematic manner. We will develop and validate an imaging prognostic score, termed the Tau Progression Index (TPI), to better predict the future accumulation of tau, neurodegeneration, and cognitive impairment, based on the subject’s individual brain structural and functional connectivity, as well as patterns of tau and amyloid deposition.