The Contribution of Age-Related Taupahtoies to Alzheimer's Disease-Supplement

Establishing an accurate neuropathological diagnosis is a critical function of Alzheimer’s Disease Research Center (ADRC) Neuropathology Cores and is a prerequisite for all tissue-based research. Chronic traumatic encephalopathy (CTE), primary age-related tauopathy (PART), argyrophilic grain disease (AGD) and aging- related tau astrogliopathy (ARTAG) are all age-related tauopathies, yet each has distinctive patterns of abnormal tau deposition. Criteria to diagnose CTE, PART, AGD and ARTAG have been recently proposed, yet no modules exist to capture these disorders in the National Alzheimer’s Disease Coordinating Center (NACC) database. Without rigorous, reproducible protocols for the diagnosis of age-related tauopathies, disease-specific contributors to late life cognitive decline might be overlooked, confused, and obscured. Twenty-nine Alzheimer Disease Research Centers across the U.S. contribute neuropathological data to the National Alzheimer's Coordinating Center - Neuropathology Data Set (NACC-NDS), making the NACC-NDS one of the largest publicly accessible neuropathological datasets on AD and related disorders in the world. In this proposal we will draw on the neuropathological expertise of Dr. Ann McKee, Dr. Dennis Dickson, and Dr. John Crary, who have pioneered investigations of CTE, AGD and PART. We will use 152 cases of AD and age-related tauopathies from the Boston University, Mayo Clinic Jacksonville, and Mount Sinai ADCs to identiify novel tau and inflammatory markers to detect and distinguish the disorders. We will also establish the frequency of CTE, PART, AGD and ARTAG among 600 cognitively normal, mild cognitively impaired and demented subjects in the NACC-NDS with NACC-Uniform Data Set (UDS) diagnosis and determine the contribution of these disorders to clinical diagnosis and cognitive and neuropsychiatric profile. We will apply knowledge gained from this project to develop CTE, PART, AGD and ARTAG assessment modules and provisional criteria to neuropathologically differentiate the age-related tauopathies for general use. This proposal will answer a critically unmet need in the study of neurodegeneration. Specifically, it will identify novel tau and neuroinflammatory markers in CTE, PART, AGD and ARTAG to aid in their detection and discrimination. This project will also determine the frequency of these age-related tauopathies among memory disorder clinic patients and determine whether these disorders contribute to the clinical profile. In addition, this project will develop a digital library of immunostained slides from 600 NACC cases (200 normal cognition, 200 MCI, 200 dementia) with UDS phenotyping that will be available to other ADRC and NACC investigators. This research has the potential to transform the way we conceptualize MCI and dementia, and ultimately, develop more effective therapeutic strategies, by developing harmonized criteria for the diagnosis of distinct disorders that contribute to the clinical diagnosis, cognitive and neuropsychiatric profile, and neuropathological phenotype of memory disorders patients.