Integrated multimodal cell atlas of Alzheimer’s disease
Authors: Gabitto Mariano , Travaglini Kyle , Ariza Jeannelle , Kaplan Eitan , Long Brian , Rachleff Victoria , Ding Yi , Mahoney Joseph , Dee Nick , Goldy Jeff , Melief Erica , Brouner Krissy , Compos Jazmin , Campos John , Carr Ambrose , Casper Tamara , Chakrabarty Rushil , Clark Michael , Cool Jonah , Dalley Rachel , Darvas Martin , Dolbeare Tim , Ding Song-Lin , Egdorf Tom , Esposito Luke , Ferrer Rebecca , Gala Rohan , Gary Amanda , Gloe Jessica , Guilford Nathan , Guzman Junitta , Ho Windy , Jarsky Tim , Johansen Nelson , Kalmbach Brian , Keene Lisa , Khawand Sarah , Kilgore Mitchell , Kirkland Amanda , Kunst Michael , Lee Brian , Donald Christine Mac , Malone Jocelin , Maltzer Zoe , Martin Naomi , McCue Rachel , McMillen Delissa , Meyerdierks Emma , Meyers Kelly , Mollenkopf Tyler , Montine Mark , Nolan Amber , Nyhus Julie , Olsen Paul , Pacleb Maiya , Pham Trangthanh , Pom Christina , Postupna Nadia , Ruiz Augustin , Schantz Aimee , Sorensen Staci , Staats Brian , Sullivan Matt , Sunkin Susan , Thompson Carol , Tieu Michael , Ting Jonathan , Torkelson Amy , Tran Tracy , Cuevas Nasmil Valera , Wang Ming-Qiang , Waters Jack , Wilson Angela , Haynor David , Gatto Nicole , Jayadev Suman , Mufti Shoaib , Ng Lydia , Mukherjee Shubhabrata , Crane Paul , Latimer Caitlin , Levi Boaz , Smith Kimberly , Close Jennie , Miller Jeremy , Hodge Rebecca , Larson Eric , Grabowski Thomas , Hawrylycz Michael , Keene C. , Lein Ed 
Published: May 2023

Alzheimer’s disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive 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 the BRAIN Initiative Cell Census Network experimental practices, combining quantitative neuropathology with single cell genomics and spatial transcriptomics, to understand the impact of disease progression on middle temporal gyrus cell types. We used quantitative neuropathology to place 84 cases spanning the spectrum of AD pathology along a continuous disease pseudoprogression score. We used multiomic technologies to profile single nuclei from each donor, mapping their identity 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 at SEA-AD.org.