Defining the effect of Alzheimer pathologies on the aged brain in 3 dimensions

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This proposal, to create the 3D Aging & Alzheimer Brain Program, addresses several critical gaps in ongoing efforts to bridge the divide between known risk factors for Alzheimer’s disease (AD) and the syndromic manifestations of the disease. The significant gaps are in: i) how the neurobiology of aging-related cognitive decline may provide insights into enhancing resilience; ii) understanding the molecular mechanisms of AD susceptibility loci and diversification of AD target genes and how these genes cause a cellular effect; and iii) key topological and morphometric information when using current sequencing approaches on cortical tissue to implicate cellular subtypes contributing to disease. To address these gaps, we propose a comprehensive program to systematically generate and analyze multiple interconnected reference data sets, that includes diverse individuals, to (a) characterize the individual and synergistic effects that AD proteinopathies, cerebral amyloid angiopathy (CAA), and aging itself have on the molecular and cellular architecture of the older neocortex and (b) identify those aspects that contribute to cognitive decline, the clinically meaningful outcome of AD. To this end, our Program targets three brain regions to capture the effects of a range of different neuropathologies. We will establish three large-volume molecular atlases of: 1) the aging brain by sampling the entire lifespan in individuals with minimal neuropathologic burden to investigate the effect of aging itself in the brain; 2) the impact of amyloid and tau proteinopathies, including specific representative cases to capture the independent and synergistic effects of β-amyloid and tau alone and in combination with α-synuclein and TDP-43 proteinopathies; and 3) the impact of CAA to yield new insights into a very different aspect of amyloid proteinopathy and its impact on the neurovascular unit. We will then establish a reference dataset of molecular data in 300 diverse individuals to enable the assessment of spatial molecular features in relation to pathological and cognitive outcomes. In parallel to the development of these atlases and reference datasets, we will optimize experimental protocols for spatial transcriptomics and iterative indirect immunofluorescence imaging (4i) to facilitate large-scale projects and enable enhanced data generation over existing, baseline capabilities. We will distribute all protocols and data through the NIA-funded AD Knowledge portal, which already hosts multiomic data from the same cohorts and participants, to accelerate repurposing of the data. Finally, we will create MAAP-Brain, a 3-D interactive data visualizer, so that all investigators and particularly non-computational scientists, can interact with our data and results. The Program team brings together a highly complementary cast of talented junior and senior scientists, and it rests on a foundation of multiple intersecting long-term collaborative research programs that position it well to achieve all its deliverables towards advancing our understanding of the complex clinico-spatial-molecular features that contribute to aging and AD, which will provide needed resources to the broader scientific community.