Project 4: Integrative analysis of spatial molecular features and clinico-pathological characteristics

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PROJECT 4: PROJECT SUMMARY/ABSTRACT Over the past two decades, we have come to appreciate that the aging brain harbors a multiplicity of neuropathologies and that AD proteinopathy often coexists with other pathologic features such as Lewy Bodies and TDP43 proteinopathy. However, the impact of co-occurrence remains poorly understood. Co-occurrence also increases with advancing age, highlighting that age is a critical risk factor for all of the neuropathologies that we examine in our 3D Aging & Alzheimer Brain Program. This project aims to profile brain tissue from a large (n=300) set of diverse individuals to create a complementary resource to those produced in Projects 1-3. Here, we profile a random sample of participants in the RUSH cohorts to capture the heterogeneity seen in the older population. In addition, we leverage their detailed ante-mortem characterization of neuropsychologic function to relate molecular data and the cellular attributes identified in Projects 1-3 to cognitive decline, the ultimate, clinically meaningful outcome in AD. Amyloid, tau and CAA all influence cognitive performance in the ROSMAP cohorts. In particular, preliminary results from single nucleus RNAseq data suggest a critical role for a new microglial subtype, Microglia 13 (Mi13), in AD and CAA. Thus, the new 3D dataset that we propose to generate and distribute as part of this Project will enable us to test a specific hypothesis that we have today and to uncover new insights from unbiased analyses. Our samples also include 100 African-American (AA) participants from the ROSMAP and MARS cohorts that have the same clinicopathologic traits and multiomic brain data as the 200 non-hispanic white (NHW) participants. Here, we therefore explicitly complement the other Projects, which focus on Non-Hispanic White participants, by sampling a large number of AA subjects so that we can assess the generalizability of our findings to a broader population. The integrated analysis of the data in this project with the attributes identified in the other three projects will lead to a new set of candidate proteins involved in cognitive decline, which will be used to profile a replication cohort of an independent set of participants. Thus, the key goals for us are (1) the creation of an easily repurposable, high-impact dataset, (2) the testing of a current hypothesis and (3) assembly of an important set of new insights into AD and CAA that can be used to seed further investigation, including some dedicated to AA. Overall, this Project creates a unique reference data set that can be repurposed for a multitude of uses and leveraged to design a next generation of spatial transcriptomic (ST) studies for other neurodegenerative diseases.