Project Summary/Abstract. Advanced biomarker mapping has led to the current understanding that Alzheimer’s disease (AD) is an extremely complex neurodegenerative disorder, with substantial heterogeneity in temporal and spatial characteristics of the classical amyloid and tau pathologies and resultant neurodegeneration among patients (as described by the amyloid-tau-neurodegeneration, ‘A-T-N’ biological framework that is the new standard for characterizing the neuropathology of AD). This complexity is a major barrier to clinical care and to the development of effective therapies, highlighting the importance of integrated biomarker neuromapping for understanding AD. However, substantial challenges remain in the neuropathologic characterization of patients. Current procedures for mapping the neurodegenerative component (N) of AD are limited in sensitivity to early pathology. Additionally, the specific biomarkers of the amyloid- and tau-based primary AD neuropathologies are only available through relatively invasive and/or expensive positron emission tomography (PET) and lumbar puncture (LP) cerebrospinal fluid (CSF) procedures in specialized laboratories and clinics. We aim here to advance AD neuropathology mapping on multiple levels: 1) we will implement a novel multi-scale structural mapping (MSSM) MRI procedure for sensitive quantification of the neurodegeneration component of AD; 2) we will use the MSSM procedure to differentially predict amyloid and/or tau positivity in symptomatic and asymptomatic individuals, providing a highly accessible method for pathology detection when advanced biomarkers are not available; 3) we will create individualized ‘A-T-N’ brainmaps through the integration of the MSSM metrics with existing PET amyloid and tau data; and 4) we will use MSSM features for the regional prediction of amyloid and tau pathology for use when PET data are not available. Our Specific Aims are: Aim 1. To test the accuracy of a novel MSSM procedure for probabilistic classification of symptomatic and asymptomatic individuals as being amyloid “positive” or tau “positive.” Hypothesis 1a (H1a). We hypothesize that MSSM ‘N’ metric can be used with a high level of sensitivity to predict whether an individual is A+ measured via PET using standard thresholds and/or T+ measured via PET using standard thresholds, or both. H1b. MSSM will provide better separation of individuals as N+ vs. N- than conventional MRI-based atrophy measures, validated through concordance with molecular pathology and clinical progression. Aim 2. To utilize the novel MSSM features for synthesis of PET-like maps of AD neuropathologic change. H2a. MSSM features will provide accurate spatial prediction of specific regional neuropathologic changes. Prediction accuracy will be measured against independent in vivo datasets including a subset with autopsy confirmation and regional quantification of plaques, tangles, and neuronal loss. Successful MSSM implementation would greatly advan...