A network for diverse cohort selection, precision tissue preparation and quantitative neuropathological characterization of Alzheimer's Disease and comorbid dementias.

Allen Institute, Seattle WA

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Abstract

ABSTRACT (PROJECT 1) The overarching goal of Project 1 is to facilitate development of a diverse cohort of brain donors across the spectrum of Alzheimer’s disease (AD) and AD-related comorbid dementias (ADRD) with optimally preserved and characterized brain tissues for multimodal analysis including integrated diagnostic and quantitative neuropathology (Project 1), next generation single nucleus Multiome (Project 2), and spatial transcriptomics and proteomics (Project 3). To accomplish this, we propose to create a multisite Neuropathology Core Network (NCN) where we apply state-of-the-art methods to build a diverse pool of brain donor candidates for SEA-AD2.0 with optimally preserved and characterized tissues spanning AD and AD/ADRD (Aim 1). We propose a national network of ADRC neuropathology cores and community-based studies that have or will adopt modern tissue collection and characterization methods that will then be applied to all prospective donors. Donor brains from the NCN will undergo thorough neuropathological examination with oversight of a Neuropathology Consensus Panel (NCP) to promote consistent application of standard criteria and to develop and test novel diagnostic criteria that may benefit the broader neuropathology community. From the NCN donors, we will assemble a SEA-AD2.0 donor cohort with guidance from a Diversity and Donor Selection Committee whose members include experts in neuroethics, neurodiagnostics, and clinical and basic neuroscience (Aim 2). Our goal is to build a diverse and deeply phenotyped SEA-AD 2.0 cohort including donors from underrepresented racial and ethnic backgrounds and/or with early AD neuropathology or AD plus AD-related comorbid dementias/pathologies, cognitively normal aged donors without AD pathology (resistance) or those with high levels of AD pathology (resilience). We will prioritize donors with rich longitudinal clinical and biomarker characterization for inclusion in the SEA-AD2.0 cohort. Once selected, 3D brain surface scanning and high-resolution photographic data from each site will be used for volumetric reconstruction of each brain, registration with a common coordinate framework, and parcellation of brain slice images to maximize anatomical precision for sampling and downstream analyses. In Aim 3, we apply advanced quantitative neuropathological methods to precisely map neurodegeneration across the brain to inform single nucleus (Project 2) and spatial (Project 3) -omics studies. Fixed tissues from multiple brain regions will be sent to UW from each NCN site to be stained, scanned, and annotated for multifactorial quantitative neuropathological analysis focused on pathologic peptide burden, neuronal and glial populations and morphologies, and neuroinflammation. We have selected five core brain regions that capture the broad range of AD and AD/ADRD pathological progression, and up to 20 additional regions to enhance coverage of early pathology, of functionally relevant areas within connectivity networks, and areas that subserve specific cognitive domains in AD. When completed, Project 1 will have created a diverse cohort with optimally preserved and characterized tissues for multimodal neuropathological and molecular analyses designed to identify early vulnerable cells and mechanistic pathways in AD and AD/ADRD.