Integrated multimodal cell atlas of Alzheimer’s disease
Authors: Gabitto Mariano I. , Travaglini Kyle J. , Rachleff Victoria M. , Kaplan Eitan S. , Long Brian , Ariza Jeanelle , Ding Yi , Mahoney Joseph T. , Dee Nick , Goldy Jeff , Melief Erica J. , Brouner Krissy , Campos Jazmin , Campos John , Carr Ambrose J. , Casper Tamara , Chakrabarty Rushil , Clark Michael , Cool Jonah , Valera Cuevas Nasmil J. , Dalley Rachel , Darvas Martin , Ding Song-Lin , Dolbeare Tim , Mac Donald Christine L. , Egdorf Tom , Esposito Luke , Ferrer Rebecca , Gala Rohan , Gary Amanda , Gloe Jessica , Guilford Nathan , Guzman Junitta , Hirschstein Daniel , Ho Windy , Jarksy Tim , Johansen Nelson , Kalmbach Brian E. , Keene Lisa M. , Khawand Sarah , Kilgore Mitch , Kirkland Amanda , Kunst Michael , Lee Brian R. , Malone Jocelin , Maltzer Zoe , Martin Naomi , McCue Rachel , McMillen Delissa , Meyerdierks Emma , Meyers Kelly P. , Mollenkopf Tyler , Montine Mark , Nolan Amber L. , Nyhus Julie , Olsen Paul A. , Pacleb Maiya , Peña Nicholas , Pham Thanh , Pom Christina Alice , Postupna Nadia , Ruiz Augustin , Schantz Aimee M. , Shapovalova Nadiya V. , Sorensen Staci A. , Staats Brian , Sullivan Matt , Sunkin Susan M. , Thompson Carol , Tieu Michael , Ting Jonathan , Torkelson Amy , Tran Tracy , Wang Ming-Qiang , Waters Jack , Wilson Angela M. , Haynor David , Gatto Nicole , 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 , Dirk Keene C. , Lein Ed S. 
Published: May 2023

AbstractAlzheimer’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. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research atSEA-AD.org.