Translational Capabilities: Single cell molecular profiling

Support standardized, single cell molecular profiling (genomic, proteomic, metabolomic) and open-access data infrastructure to develop a single-cell atlas for the aging brain and for AD/ADRD that can be queried by data scientists as well as basic and clinical researchers. The selection of samples for single-cell profiling needs to be optimized to allow integration of molecular profiles with existing clinical and whole-tissue molecular data (from brain and peripheral tissues) generated on the same individuals to aid novel target and biomarker discovery for precision medicine.

Support the development of integrative, computational models of cellular interactions in the CNS underlying brain aging and transition to AD and ensure their rapid and wide dissemination to the research community. These efforts should include research on:

i) understanding cell-specific vulnerability to amyloid ß, tau and other pathogenic insults, and

ii) neuron-glia, glia-glia, and other inter-cellular interactions in the context of brain aging and AD/neurodegeneration.

2024 RFA-AG-17-054: Enhancing the Target and Biomarker Discovery Efforts of the AMP AD and M2OVE-AD Consortia (R01) RFA-AG-18-013: Continuation of the AMP AD Target Discovery and Preclinical Validation Consortium RFA-AG-18-014: Limited Competition: Data Coordinating Center for the Accelerating Medicines Partnership Target Discovery and Preclinical Validation Consortium AMP AD (U24) RFA-AG-21-033: Regulation of Brain Regional and Cell Type Specific Proteome Dynamics in Aging and Alzheimer's Disease (R01 Clinical Trial Not Allowed) 4.L Achieved Support standardized, single cell molecular profiling (genomic, proteomic, metabolomic)... DN 2018 AD Summit: 1D, 1E, 1F, 2K and 3C 2021 AD Summit: 1.J News: Gene expression signatures of Alzheimer's disease News: Aging may change some brain cells more than others News: Alzheimer’s disease may damage the brain in two phases Translational Tools, Infrastructure, and Capabilities A platform for cell type-level transcriptomic, epigenomic and spatial interrogation of Alzheimer’s disease Next Generation Translational Proteomics for Alzheimer’s and Related Dementias AMP AD 2.0 Precision Medicine Approach to Target and Biomarker Discovery Defining the effect of Alzheimer pathologies on the aged brain in 3 dimensions Alzheimer’s Disease Multimodal Atlas Projects (AD-MAPs) Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD)

  • Launch a program to support deep single-cell molecular profiling using cells from participants from at least 6 diverse cohorts to complement whole brain and peripheral tissue molecular profiling conducted in the same participants. Provide support for adequate hosting, curation, analyses and mining of the datasets and network models via existing and/or new data sharing platforms.
  • Develop links between the AD/ADRD research community and the research community supported by the BRAIN Initiative's Cell Census efforts to accelerate the development of new cell type-selective molecular genetic tools, new model systems and gene therapy-based therapeutics.

Summary of Key Accomplishments

NIA supports a large multi-component project that aims to improve AD brain tissue banking and analysis and to adapt cutting edge single-cell profiling methods. These tools will be used to generate understanding of the molecular and structural progression of AD and create a high-quality, open-access dataset for the research community.

As part of the second phase of the AMP-AD program, NIA supports single-nucleus/single-cell molecular profiling using brain samples from participants from diverse cohorts. Large-scale single-cell profiling efforts are also supported through the Psych-AD and Resilience-AD programs. All data generated through these programs are being made available to the research community through the NIA-supported AD Knowledge Portal.

Building on progress by the BRAIN Initiative Cell Census Network and the BRAIN Initiative Cell Atlas Network to chart the molecular identities and spatial organization of cell types in the brains of multiple species, NIA supports a family of projects—known as AD-Multimodal Atlasing Projects (AD-MAPs)—that extends this approach to discover how changes in cell types and in cellular assemblies called circuits underlie aging and AD. The Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD) Consortium, a cornerstone of AD-MAPs, utilizes advanced technologies from the BRAIN Initiative with the goal of producing the highest-resolution brain-wide human cell atlas of AD.

NIA is also building on another transformative program of the BRAIN Initiative, the Armamentarium for Precision Brain Cell Access, which develops new technologies to monitor and manipulate brain cell types with extreme precision. Complementary to the goal of AD-MAPs to identify brain cell types that are important in AD, NIA published a funding opportunity in May 2024 to promote use of BRAIN Initiative tools to precisely target these cell types to answer questions related to aging and AD.

The key accomplishments summary is current as of June 2024.