Integrated multimodal cell atlas of Alzheimer's disease

• Published in: bioRxiv
• Main Authors: Gabitto, Mariano I, Travaglini, Kyle J, Rachleff, Victoria M, Kaplan, Eitan S, Long, Brian, Ding, Yi, Mahoney, Joseph T, Dee, Nick, Goldy, Jeff, Melief, Erica J, Agrawal, Anamika, Kana, Omar, Xingjian Zhen, Barlow, Samuel T, Brouner, Krissy, Campos, Jazmin, Campos, John, Carr, Ambrose J, Chakrabarty, Rushil, Clark, Michael, Cool, Jonah, Dalley, Rachel, Darvas, Martin, Dolbeare, Tim, Egdorf, Tom, Esposito, Luke, Ferrer, Rebecca, Fleckenstein, Lynn E, Gala, Rohan, Gary, Amanda, Gelfand, Emily, Guilford, Nathan, Guzman, Junitta, Hirschstein, Daniel, Ho, Windy, Hupp, Madison, Jarksy, Tim, Johansen, Nelson, Kalmbach, Brian E, Keene, Lisa M, Khawand, Sarah, Kilgore, Mitch, Kirkland, Amanda, Kunst, Michael, Lee, Brian R, Leytze, Mckaila, Mac Donald, Christine L, Malone, Jocelin, Maltzer, Zoe, Mccue, Rachel, Mcmillen, Delissa, Mena, Gonzalo, Meyerdierks, Emma, Meyers, Kelly P, Mollenkopf, Tyler, Montine, Mark, Nolan, Amber L, Nyhus, Julie, Olsen, Paul A, Pacleb, Maiya, Pagan, Chelsea M, Pena, Nicholas, Pham, Trangthanh, Pom, Christina A, Rimorin, Christine, Ruiz, Augustin, Saldi, Giuseppe A, Schantz, Aimee M, Shapovalova, Nadiya V, Sorensen, Staci A, Staats, Brian, Sullivan, Matt, Sunkin, Susan M, Thompson, Carol, Tieu, Michael, Ting, Jonathan, Torkelson, Amy, Nasmil J Valera Cuevas, Walling-Bell, Sarah, Ming-Qiang, Wang, Waters, Jack, Wilson, Angela M, Haynor, David, Gatto, Nicole M, Jayadev, Suman, Mufti, Shoaib, Ng, Lydia, Mukherjee, Shubhabrata, Crane, Paul K, Latimer, Caitlin S, Levi, Boaz P, Smith, Kimberly, Close, Jennie L, Miller, Jeremy A, Hodge, Rebecca D, Larson, Eric B, Grabowski, Thomas J, Hawrylycz, Michael, Keene, C Dirk, Lein, Ed S
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.02.2024
• Subjects: Alzheimer's disease; Cognitive ability; Cortex (temporal); Dementia disorders; Gene mapping; Inflammation; Myelination; Neurodegenerative diseases; Neuroimaging; Oligodendrocytes; Pathology; Prefrontal cortex; Temporal gyrus; Transcriptomes
• DOI: 10.1101/2023.05.08.539485

Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Pseudo-progression analysis showed two major epochs corresponding with a slow early increase in pathology and a later exponential increase that correlated with cognitive decline. The early phase included inflammatory microglial and reactive astrocyte component, as well as a selective loss of Sst+ inhibitory neuron types in superficial cortical layers, loss of myelinating oligodendrocytes, and up-regulation of a re-myelination program by OPCs. The later phase involved loss of excitatory neurons and Pvalb and Vip neuron subtypes also predominantly in superficial layers. These cell vulnerabilities were also seen in prefrontal cortex and replicated by other independent studies when integrated with the BRAIN Initiative reference. Study data and exploratory tools are freely available to accelerate progress in AD research at SEA-AD.org.Competing Interest StatementThe authors have declared no competing interest.Footnotes* The revised manuscript now features: 1) Description of a single nucleus RNA sequencing dataset generated from a new cortical region, the dorsolateral prefrontal cortex (DLPFC) 2) An integrated atlas across 10 publicly available single cell studies that also profiled the DLPFC in AD donors 3) New data and analysis of MERFISH spatial analyses 4) Additional analyses on non-neuronal cells* http://sea-ad.org* https://adknowledgeportal.synapse.org/Explore/Studies/DetailsPage?Study=syn26223298* https://registry.opendata.aws/allen-sea-ad-atlas/