Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD)

Introduction

Overview

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    AD["AD"] -->|"causes"| memory_loss["memory_loss"]
    AD["AD"] -->|"associated with"| TAU["TAU"]
    AD["AD"] -->|"causes"| IMMUNE_TOL["IMMUNE_TOL"]
    AD["AD"] -->|"causes"| DEMENTIA["DEMENTIA"]
    AD["AD"] -->|"inhibits"| cholinergic_transmission["cholinergic_transmission"]
    AD["AD"] -->|"regulates"| PROTEOME["PROTEOME"]
    AD["AD"] -->|"associated with"| CHOLINERGIC_TRANSMISSION["CHOLINERGIC_TRANSMISSION"]
    AD["AD"] -->|"associated with"| GLYCOLYTIC_PATHWAY["GLYCOLYTIC_PATHWAY"]
    TDP_43["TDP-43"] -->|"associated with"| Ad["Ad"]
    TAU["TAU"] -->|"implicated in"| AD["AD"]
    TAU["TAU"] -->|"associated with"| AD["AD"]
    APOE["APOE"] -->|"associated with"| AD["AD"]
    MIR_146A["MIR-146A"] -->|"associated with"| AD["AD"]
    style AD fill:#4fc3f7,stroke:#333,color:#000

The Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD) is a large-scale, multi-institutional research consortium dedicated to gaining a deep molecular and cellular understanding of the early pathogenesis of Alzheimer’s Disease (AD). The project creates the most comprehensive open-access cellular atlas of AD, integrating neuropathology, single-cell and spatial genomics, whole genome sequencing, and longitudinal clinical metadata from human brain tissue spanning the full spectrum of Alzheimer’s Disease pathology ^{9SEA-AD is a multimodal cellular atlas and resource for Alzheimer's Disease (2024)2024 · DOI 10.1038/s43587-024-00719-8Open reference}.

SEA-AD is led by the Allen Institute for Brain Science in collaboration with the University of Washington Alzheimer’s Disease Research Center (UW ADRC) and the Kaiser Permanente Washington Health Research Institute, which operates the Adult Changes in Thought (ACT) longitudinal aging study. The project is supported by the National Institute on Aging (NIA) under award U19AG060909. As of 2026, public consortium resources remain active (including a refreshed SEA-AD portal and a 2026 consortium/SAB update meeting), so prior wording that implied work ended in 2025 should be interpreted as the initial award-cycle framing rather than project closure

The consortium’s goal is to identify which brain cell types are affected earliest in AD, what molecular changes drive the disease, and how these changes relate to the progression of amyloid plaques, tau tangles, and cognitive decline. By making all data freely available, SEA-AD aims to accelerate the development of cell-type-specific therapeutic targets for AD.

Consortium Partners

Allen Institute for Brain Science

The Allen Institute for Brain Science serves as the lead institution, providing expertise in large-scale single-cell genomics, spatial transcriptomics, and data integration. Key Allen Institute investigators include:

• Ed Lein, Ph.D. — Principal Investigator, head of the Human Cell Types Department

• Mariano I. Gabitto, Ph.D. — Co-lead of data analysis, lead author of the 2024 integrated atlas

• Kyle J. Travaglini, Ph.D. — Co-lead of SEA-AD computational analysis

• Michael Hawrylycz, Ph.D. — Data analysis and annotation

• Rebecca Hodge, Ph.D. — Human cell type classification

• Jeremy Miller, Ph.D. — Cell taxonomy and spatial analysis

• Boaz Levi, Ph.D. — Genomics and molecular profiling

University of Washington ADRC

The UW Alzheimer’s Disease Research Center provides clinical expertise, neuropathological assessment, and access to brain tissue from research participants with well-characterized clinical histories. The UW ADRC contributes post-mortem brain tissue with extensive antemortem clinical data including cognitive assessments and medical history.

Kaiser Permanente Washington Health Research Institute

The Adult Changes in Thought (ACT) study, based at Kaiser Permanente Washington, is a long-running prospective cohort study that has followed thousands of older adults in the Seattle area since 1994. ACT participants contribute to SEA-AD by providing longitudinal cognitive data and consenting to brain donation upon death, enabling researchers to link cellular changes to clinical progression over years or decades ^{2Allen Institute news: Landmark study traces Alzheimer's pathological clock (2024)2024Open reference}2.

Data Modalities

SEA-AD integrates an unprecedented breadth of data types from each donor brain, enabling multiscale analysis from molecules to cells to tissue architecture:

Single-Nucleus Transcriptomics (snRNA-seq)

Using 10x Genomics Chromium technology, researchers have profiled gene expression from millions of individual nuclei isolated from the middle temporal gyrus (MTG) of 84 donors. Over 36,000 genes are evaluated per nucleus, enabling identification of more than 100 cell types in each cortical area assayed. This includes all major neuronal subtypes (excitatory and inhibitory), astrocytes, oligodendrocytes, microglia plaque density and distribution

• Tau(/proteins/tau neurofibrillary tangle burden (Braak staging)

• CERAD neuritic plaque score

• TDP-43 inclusions

• Lewy body pathology

• Cerebrovascular disease indicators

Clinical Metadata

Each donor’s brain tissue is accompanied by longitudinal clinical data including cognitive test scores, dementia diagnosis history, comorbidities, medications, and demographic information. This linkage between molecular data and clinical phenotype is critical for understanding how cellular changes drive the clinical progression of AD ^{2Allen Institute news: Landmark study traces Alzheimer's pathological clock (2024)2024Open reference}3.

Key Findings

Two-Phase Model of Alzheimer’s Disease Progression

The SEA-AD consortium’s landmark paper, published in Nature Neuroscience in October 2024 by Gabitto, Travaglini, Rachleff et al., analyzed 3.4 million brain cells from 84 donors and revealed that Alzheimer’s Disease progresses through two distinct phases ^{2Allen Institute news: Landmark study traces Alzheimer's pathological clock (2024)2024Open reference}4:

Early Phase (Slow Pathology Accumulation):

• Gradual, slow increase in amyloid and tau] pathology

• Activation of inflammatory microglia/cell-types/microglia — immune cells shift to a disease-associated state

• Reactive astrocytes — support cells become inflammatory

• Selective loss of somatostatin-positive (SST+) inhibitory neurons — the earliest neuronal casualties

• Compensatory remyelination response by oligodendrocyte precursor cells (OPCs)

• Cognitive function may be relatively preserved during this phase

Late Phase (Exponential Pathology Increase):

• Dramatic, exponential increase in amyloid plaques and tau tangles

• Loss of multiple neuronal types — both excitatory and inhibitory neurons

• Sustained microglial and astrocyte inflammation

• Decline in oligodendrocyte activity and remyelination capacity

• Widespread neuronal death leading to severe cognitive decline and dementia

Surprise: Inhibitory Neuron Vulnerability

A key finding of the SEA-AD study was that somatostatin-expressing (SST+) inhibitory interneurons are selectively lost in the earliest phase of AD — before the widespread excitatory neuron death that characterizes later stages. This was unexpected, as most prior research had focused on excitatory neurons and cholinergic neurons as the primary casualties of AD ^{2Allen Institute news: Landmark study traces Alzheimer's pathological clock (2024)2024Open reference}5.

The researchers hypothesize that loss of SST+ inhibitory neurons may trigger a cascade of dysfunction: disrupting the balance between excitation and inhibition in cortical circuits, leading to hyperexcitability, aberrant neural activity, and ultimately widespread network collapse. This finding has implications for understanding epileptiform activity observed in early AD and may point to new therapeutic targets ^{2Allen Institute news: Landmark study traces Alzheimer's pathological clock (2024)2024Open reference}6.

Cell-Type-Specific Gene Regulatory Changes

By combining snRNA-seq and snATAC-seq (Multiome) data, SEA-AD has identified disease-associated changes in gene regulatory programs that are specific to individual cell types. For example, microglia show activation of inflammatory pathways (including complement, cytokine signaling, and phagocytosis genes), while astrocytes show changes in glutamate metabolism and calcium signaling genes ^{2Allen Institute news: Landmark study traces Alzheimer's pathological clock (2024)2024Open reference}7.

Spatial Organization of Pathology

MERFISH spatial transcriptomics data reveals how cell types are reorganized around pathological features. Disease-associated microglia/cell-types/microglia cluster near amyloid plaques, while reactive astrocytes form a surrounding layer — creating a “cellular halo” of inflammation around each plaque. These spatial patterns intensify with disease severity ^{2Allen Institute news: Landmark study traces Alzheimer's pathological clock (2024)2024Open reference}8.

Implications for Therapeutics

The SEA-AD findings have significant implications for therapeutic development:

1. Timing of intervention: The two-phase model suggests that therapeutic interventions (particularly anti-amyloid and anti-inflammatory approaches) may be most effective during the early, slow phase before pathology becomes exponential ^{2Allen Institute news: Landmark study traces Alzheimer's pathological clock (2024)2024Open reference}9.

2. Cell-type-specific targets: Knowledge of which cell types change earliest (SST+ inhibitory neurons, microglia, astrocytes) provides new therapeutic targets that could be addressed before widespread neuronal loss ^{3NIH news release: Alzheimer's Disease may damage the brain in two phases (2024)2024Open reference}0.

3. Biomarker development: Cell-type-specific molecular signatures identified by SEA-AD could be developed into blood-based biomarkers for earlier AD detection ^{3NIH news release: Alzheimer's Disease may damage the brain in two phases (2024)2024Open reference}1.

4. Precision medicine: Integration of genetic data (WGS) with cell-type-specific changes enables identification of genotype-specific disease mechanisms, supporting precision medicine approaches ^{3NIH news release: Alzheimer's Disease may damage the brain in two phases (2024)2024Open reference}2.

Data Access and Resources

All SEA-AD data is freely available to the research community through multiple portals:

• SEA-AD Data Portal: portal.brain-map.org/explore/seattle-alzheimers-disease

• CZ CELLxGENE: cellxgene.cziscience.com — interactive cell atlas visualization

• AWS Open Data: registry.opendata.aws/allen-sea-ad-atlas — raw data download

• NIAGADS DSS: dss.niagads.org/studies/sa000065 — National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site

• GitHub: github.com/AllenInstitute/SEA-AD_2024 — analysis code and notebooks

Resources include interactive visualization tools, downloadable cell count matrices, metadata tables, spatial maps, and reproducible analysis notebooks.

Relationship to Other Projects

SEA-AD is part of a broader ecosystem of brain cell atlas projects:

• BRAIN Initiative Cell Census Network (BICCN/BICAN): SEA-AD uses cell type reference atlases created by the BRAIN Initiative to classify disease-affected cell populations

• Allen Brain Cell (ABC) Atlas: SEA-AD builds on the comprehensive whole-brain cell type taxonomy developed by the Allen Institute

• Human Cell Atlas (HCA): SEA-AD contributes human brain cell data to the international Human Cell Atlas consortium

• Aging, Dementia and TBI Study: A complementary Allen Institute project studying aging and traumatic brain injury (aging.brain-map.org)

See Also

• Astrocytes

• microglia/cell-types/microglia

• Oligodendrocytes

• Allen Institute

External Links

• SEA-AD Portal

• About SEA-AD

• SEA-AD Data Downloads

• Allen Institute Alzheimer’s Research

• SEA-AD on CZ CELLxGENE

Background

The study of Seattle Alzheimer’S Disease Brain Cell Atlas (Sea Ad) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.