The Contribution of Age-Related Tauopathies to Alzheimer's Disease

Project Abstract Establishing an accurate neuropathological diagnosis is a critical function of Alzheimer’s Disease Research Centers and a prerequisite to tissue-based research. Alzheimer’s disease (AD), chronic traumatic encephalopathy (CTE), primary age-related tauopathy (PART), progressive supranuclear palsy (PSP), argyrophilic grain disease (AGD), and aging-related tau astrogliopathy (ARTAG) are all age-related tauopathies. Each has distinctive patterns of abnormal tau deposition and clinical manifestations. While AD is the most common pathology, the other tauopathies are present in as many as 20% of brains. We recently spearheaded consensus panels to update criteria to diagnose CTE, PART, PSP, and ARTAG, yet these disorders are not captured well in the National Alzheimer’s Coordinating Center (NACC) database. During our first funding cycle, we published 29 manuscripts, showed that 4R immunostaining improves recognition of CTE in early cases and in young people, and established the roles of 4R and 3R tau, different phosphorylation epitopes, different cell types, and the utility of our staging scheme in CTE. We identified JADE1 in 4R tauopathies, the distinctive hippocampal p-tau pathology of CTE, PART vs. AD and uncovered unique neuroinflammatory proteins that distinguish CTE, PSP and AD. In addition, we showed that deep machine learning-based approaches allow recognition and quantification of tau and other pathologies and can identify novel regional and cellular features that predict dementia. We performed single nucleus RNA sequencing of oligodendrocytes and astrocytes in CTE, established a digital whole slide image (WSI) library of 150 index cases of AD, CTE, PART and AGD and developed a novel REDcap assessment protocol for tauopathies. Our long-term goal is to advance our understanding of the neuropathological signatures of the tauopathies to build a foundation for mechanistic studies that will enable new biomarkers and therapeutic targets. The objective of this proposal is to continue to identify novel markers for CTE, PART, AGD, and ARTAG, and to expand the scope to include PSP and cases from underrepresented groups. We will continue to build a digital library of WSI from 600 randomly selected, age and sex-matched NACC brain donors, including 200 people with normal cognition, 200 with mild cognitive impairment and 200 with dementia to determine if re-assessment yields previously undetected cases of the age- related tauopathies. We will examine the contribution of those pathologies to cognitive and neuropsychiatric symptoms (NPS). In addition, we will determine whether prediction of cognitive impairment and NPS is improved using supervised and unsupervised deep learning algorithms. We will also use single nucleus RNA sequencing to examine alterations in gene expression in astrocytes and oligodendrocytes in CTE, PART, PSP, vs. AGD. This proposal is significant because it will answer a critically unmet need in the study of neurodegeneration, it will establish the frequency of the age-related tauopathies in the NACC database and determine whether these tauopathies contribute to the clinical expression of cognitive and neuropsychiatric decline.