Alzheimer's Disease Resources (SEA-AD)
Overview
SEA-AD provides several resources allowing users to actively explore donor metadata, neuropathology, and cell type-specific gene expression, chromatin accessibility, and spatial localization in a cohort of donors with varying disease-associated pathologies. This page summarizes the available resources by data type, with each section summarizing why each data type is important, the kinds of questions that can be answered using the resources, and links to/brief summaries of each resource.
Examples of questions addressed by these resources include:
- In which cell types is gene X expressed?
- How does gene X change with disease in different cell types?
- What kind of cells do I have in my own omics data set?
- What is the spatial relationship between cell type X and cell type Y in AD?
- How does AD pathology look in the brains of donors with or without dementia?
- How do cell types from SEA-AD compare with cell types defined in younger donors and other cohorts?
Know your data type but not your resource—jump to the relevant section below:
Single Nucleus Transcriptomics | Spatial Transcriptomics | Donors and Neuropathology | Knowledge Intergration | Epigenomics | Whole Genome Sequencing
Single Nucleus Transcriptomics
Why single-nucleus transcriptomics data?
- Create a foundational high resolution cell type reference atlas, akin to the human genome, to understand the molecular underpinnings of Alzheimer’s disease at the cell type level.
- More than one million nuclei align to over 100 cell types in each cortical area assayed.
- Consistent cell types identified across multiple studies of AD.
Questions you can asking with these data & tools
- What cell types are found in the adult and aged brains?
- In which cells types is gene X expressed?
- Are genes X and Y co-expressed in the same cell type?
- How does gene X change with disease in different cell types?
- Which genes are most selectively expressed in a particular cell type or disease state?
- What kind of cells do I have in my own omics data set?
- Compare gene expression in cells from neurotypical and aged brains side by side for any gene
- Overlay and quantification of expression differences in the context of donor demographics and disease metrics
- Tissue assayed: middle temporal gyrus from all donors
- Visualize gene expression levels in human cortical cell types using a heatmap or a UMAP
- Tissue assayed: middle temporal gyrus from younger neurotypical donors
- These data form the basis for defining cell types in the SEA-AD aged donor cohort
- Explore gene expression levels in human cortical cells in the context of donor demographics and disease metadata using a UMAP
- Tissue assayed: middle temporal gyrus and A9 (prefrontal cortex) from all donors
- All 2.78 million nuclei are organized into a joint taxonomy to allow exploration of gene expression in the context of cell types and donor metrics
- View in parallel with SEA-AD spatial transcriptomics dataset
- Identify and visualize cell type-specific gene expression changes across AD pseudo-progression at multiple taxonomic levels
- Tissue assayed: middle temporal gyrus from aged donors
- The viewer depends on two key pieces of information: Quantitative neuropathology and gene expression - learn more in Gene Expression Trajectory Viewer's Overview
- Assign SEA-AD cell types to your own single-cell/nucleus transcriptomics data
- This application uses vetted, state-of-the-art mapping algorithms to compare your own data to SEA-AD cell type taxonomies
- Tissue assayed: middle temporal gyrus from all donors
- Perform on-the-fly analysis and visualization of gene expression and metadata from SEA-AD data sets
- Tissue assayed: datasets spanning the full taxonomy and individual subclasses in both middle temporal gyrus and A9 (prefrontal cortex)
- Note this will take you to an external website: Chan Zuckerberg Initiative's CELLxGENE
Spatial Transcriptomics
Why spatial transcriptomics data?
- Builds off the single nucleus transcriptomics data by defining the anatomical context for cell types.
- Helps address questions on how the brain-wide transcriptomics landscape of cell types relates to the anatomical and circuit organization and its ontology rooted in development and evolution.
- Spatial analyses demonstrated the co-localization of vulnerable cell populations largely in supragranular cortical layers.
Questions you can ask using these data & tools
- Where is gene X expressed in the MTG?
- What is the spatial relationship between cell type X and cell type Y?
- How does the abundance of cell type X change over the progression of AD?
- Explore cell type co-localization and gene expression in the largest cell-resolution MERFISH data set in AD human brain to date (302k cells)
- Tissue assayed: middle temporal gyrus from 24 aged donors (subset of the 84 SEA-AD cohort)
- Based on a 140 gene panel created to define neuronal types in MTG
- View in parallel with SEA-AD single nucleus dataset
Donors and Neuropathology
Data and specimens were obtained from the Adult Changes in Thought (ACT) Study from Kaiser Permanente Washington Health Research Institute (KPWHRI), and the University of Washington Alzheimer’s Disease Research Center (ADRC).
Questions you can ask using these data & tools
- What types of neuropathology are found in the aged and AD brain?
- How does AD pathology look in the brains of donors with or without dementia?
- How do amyloid, tau, and other pathologies co-occur across donors and brain regions?
- Examine images of donor brain tissue sections from multiple brain regions stained for key pathological proteins and cell types of interest to Alzheimer’s disease
- Tissue assayed: middle temporal gyrus, medial entorhinal cortex, and hippocampus
- Neuropathology from all donors can accessed via the Donor Index
Knowledge Integration
These applications aggregate and summarize information across multiple Allen Institute and community data sets, with the goal of allowing users to understand how AD-associated genes are expressed in the brain in several contexts (Gene Knowledge Cards) and compare cell type nomenclature and abundances changes with AD across studies (Annotation Comparison Explorer).
Questions you can ask using these data & tools
- In what species, brain regions, and cell types is gene X expressed in development, adult, and aged?
- Which other genes tend to be expressed in similar brain regions and cell types as gene X?
- What is cell type Y called in an earlier published study of AD?
- What SEA-AD cell type most closely relates to cluster A in my single nucleus transcriptomics data set?
- Compare cell type annotations between SEA-AD and ten community studies of AD or user data from MapMyCells
- Brain regions included: prefrontal cortex of aged/AD donors in each study
- More generally, this application can compare two or more annotations such as cell type assignments, donor information, and cell metadata across multiple of the Allen Institute's cell type data sets or in user-provided data
- Highlight patterns of gene expression in the brain and identify other genes that are related in their expression
- Integrates data from the Allen Institute’s public single-cell transcriptomics datasets and historical atlases at the level of individual genes.
- Note that this application may be slow to load as it draws data from a significant number of sources
Epigenomics: Chromatin Accessibility
Single nucleus ATAC-seq data provides access to the chromatin landscape of SEA-AD donors in health and disease, providing insights into which genes are available to be read and used to make proteins, and whether accessibility is gained or lost in AD.
Questions you can ask using these data & tools
- Where in the genome is chromatin selectively accessible in cell type X?
- Where in the genome does chromatin accessibility change in donors with high vs. low AD pathology?
- In what cell types does my known enhancer X have open chromatin?
- Explore the open chromatin landscape and assess changes in chromatin accessibilit using single nucleus ATAC-seq data
- Tissue assayed: Middle Temporal Gyrus (MTG) and A9 (Prefrontal Cortex, PFC)
- Note: this will take you external website, UCSC Genome Browser
Whole Genome Sequencing (WGS)
Whole Genome Sequencing (WGS) and Single Nucleotide Polymorphism (SNP) array data provide direct access to differences in the genetic code between SEA-AD (and other) individuals. Such differences directly impact disease risk and potential response to treatment and relate to variation in cell type-specific gene expression and chromatin accessibility between individuals.
Questions you can ask using these data
- Which SEA-AD donors have known genetic risk factors for AD and how do these factors relate to molecular changes?
- Which genomic locations impact expression of specific genes globally or in specific cell types?
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Explore Whole Genome Sequencing (WGS) and genotyping SNP array data for the SEA-AD donor cohort
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Tissue assayed: A9 (prefrontal cortex)
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Note this will take you to an external site: The National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) Data Sharing Service repository
The Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) consortium is supported by the National Institute on Aging (NIA) grant U19AG060909.
Study data were generated from postmortem brain tissue obtained from the University of Washington BioRepository and Integrated Neuropathology (BRaIN) laboratory and Precision Neuropathology Core, which is supported by the NIH grants for the UW Alzheimer's Disease Research Center (NIA grants: P50AG005136 and P30AG066509) and the Adult Changes in Thought Study (NIA grants: U01AG006781 and U19AG066567).
The ACT study is a longitudinal population-based prospective cohort study of brain aging and incident dementia in the Seattle metropolitan area. ACT is a repository at the Kaiser Permanente Washington Health Research Institute, which has established policies and procedures for sharing data with external investigators. Data available from this study web site do not require any additional Institutional Review Board (IRB) approval or permissions. Linking those data with other ACT study or Kaiser Permanente Washington data would require additional review. All of those steps are initiated after contacting KPWA.actproposals@kp.org.
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