Integrated multimodal cell atlas of Alzheimer’s disease
Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years. We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin<sup>+</sup> inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb<sup>+</sup> and Vip<sup>+</sup> inhibitory neuron subtypes. These findings were replicated in other major AD studies.
Authors
- Delissa McMillen (ORCID: https://orcid.org/0000-0002-3413-4424)
- Chelsea M. Pagan (ORCID: https://orcid.org/0000-0002-3932-9992)
- Michael Kunst (ORCID: https://orcid.org/0000-0003-4159-8056)
- Amanda Gary (ORCID: https://orcid.org/0000-0002-6397-1520)
- Brian Staats (ORCID: https://orcid.org/0000-0002-3818-3792)
- Jennie Close (ORCID: https://orcid.org/0000-0001-9234-5855)
- Mckaila Leytze (ORCID: https://orcid.org/0009-0007-1631-6703)
- Victoria M. Rachleff (ORCID: https://orcid.org/0000-0002-5003-508X)
- Brian Kalmbach (ORCID: https://orcid.org/0000-0003-3136-8097)
- Tamara Casper (ORCID: https://orcid.org/0000-0003-1638-3651)
- Amy Torkelson (ORCID: https://orcid.org/0000-0002-9465-4202)
- Rushil Chakrabarty (ORCID: https://orcid.org/0000-0003-1722-8557)
- Emma Meyerdierks (ORCID: https://orcid.org/0000-0002-6830-1438)
- Markus Hupp (ORCID: https://orcid.org/0000-0003-0845-2514)
- Naomi Martin (ORCID: https://orcid.org/0000-0002-0034-1628)
- Joseph T. Mahoney (ORCID: https://orcid.org/0000-0003-3567-3929)
- Nasmil Valera Cuevas (ORCID: https://orcid.org/0000-0002-9846-3796)
- Jonathan T. Ting (ORCID: https://orcid.org/0000-0001-8266-0392)
- Lynn E. Fleckenstein (ORCID: https://orcid.org/0009-0008-9533-7015)
- Aimee Schantz (ORCID: https://orcid.org/0009-0006-2634-4970)
- Trangthanh Pham (ORCID: https://orcid.org/0000-0002-4738-5062)
- Rebecca D. Hodge (ORCID: https://orcid.org/0000-0002-5784-9668)
- Nelson Johansen (ORCID: https://orcid.org/0000-0002-4436-969X)
- Amanda Kirkland (ORCID: https://orcid.org/0009-0006-1538-8417)
- Jazmin Campos (ORCID: https://orcid.org/0000-0002-9384-9913)
- Christine Rimorin (ORCID: https://orcid.org/0000-0003-1491-8552)
- Amber Nolan (ORCID: https://orcid.org/0000-0002-0139-0974)
- Nathan Guilford (ORCID: https://orcid.org/0000-0002-6188-7333)
- Tim Jarsky (ORCID: https://orcid.org/0000-0002-4399-539X)
- Erica J. Melief (ORCID: https://orcid.org/0000-0002-3570-3289)
- Tracy Tran (ORCID: https://orcid.org/0009-0004-4882-3388)
- C. Dirk Keene (ORCID: https://orcid.org/0000-0002-5291-1469)
- Rohan Gala (ORCID: https://orcid.org/0000-0003-1872-0957)
- Brian Long (ORCID: https://orcid.org/0000-0002-7793-5969)
- Jonah Cool (ORCID: https://orcid.org/0000-0002-0287-011X)
- Carol L. Thompson (ORCID: https://orcid.org/0000-0003-1528-3237)
- Jessica Gloe (ORCID: https://orcid.org/0000-0001-8343-3423)
- Jeremy A. Miller (ORCID: https://orcid.org/0000-0003-4549-588X)
- Caitlin S. Latimer (ORCID: https://orcid.org/0000-0003-3727-4278)
- Jeff Goldy (ORCID: https://orcid.org/0000-0001-5140-6922)
- Kyle J. Travaglini (ORCID: https://orcid.org/0000-0003-3164-6448)
- Krissy Brouner
- Michael Tieu (ORCID: https://orcid.org/0000-0001-9286-5623)
- Junitta Guzman
- Mariano I. Gabitto (ORCID: https://orcid.org/0000-0001-6911-344X)
- Julie Nyhus (ORCID: https://orcid.org/0000-0002-2006-8235)
- Daniel Hirschstein (ORCID: https://orcid.org/0009-0001-5839-6023)
- Boaz P. Levi (ORCID: https://orcid.org/0000-0002-8346-872X)
- Nadia Postupna (ORCID: https://orcid.org/0000-0002-4939-4915)
- Thomas J. Grabowski (ORCID: https://orcid.org/0000-0002-7425-6610)
- Jack Waters (ORCID: https://orcid.org/0000-0002-2312-4183)
- Rachel McCue (ORCID: https://orcid.org/0000-0003-4339-7581)
- Paul K. Crane (ORCID: https://orcid.org/0000-0003-4278-7465)
- Christina Alice Pom (ORCID: https://orcid.org/0000-0001-9057-040X)
- Martin Darvas (ORCID: https://orcid.org/0000-0002-7942-2526)
- Susan M. Sunkin (ORCID: https://orcid.org/0000-0001-9893-3834)
- Staci A. Sorensen (ORCID: https://orcid.org/0000-0002-6799-2126)
- Nadiya V. Shapovalova (ORCID: https://orcid.org/0000-0002-8618-8272)
- Shoaib Mufti (ORCID: https://orcid.org/0000-0002-8173-3884)
- Nick Dee (ORCID: https://orcid.org/0000-0002-2831-9254)
- Tyler Mollenkopf (ORCID: https://orcid.org/0000-0002-2899-2879)
- Nicole M. Gatto (ORCID: https://orcid.org/0000-0001-7873-8310)
- Jocelin Malone (ORCID: https://orcid.org/0000-0003-0794-4250)
- Anamika Agrawal (ORCID: https://orcid.org/0000-0002-1213-2321)
- Tim Dolbeare (ORCID: https://orcid.org/0000-0002-5147-1713)
- Emily Gelfand (ORCID: https://orcid.org/0000-0003-2175-5894)
- Shubhabrata Mukherjee (ORCID: https://orcid.org/0000-0003-2522-2884)
- Ambrose Carr (ORCID: https://orcid.org/0000-0002-8457-2836)
- Kimberly A. Smith (ORCID: https://orcid.org/0000-0002-3142-1970)
- Suman Jayadev (ORCID: https://orcid.org/0000-0003-3164-9665)
- Jeanelle Ariza (ORCID: https://orcid.org/0000-0002-0829-7887)
- Xingjian Zhen (ORCID: https://orcid.org/0000-0002-2220-8246)
- Ming-Qiang Wang (ORCID: https://orcid.org/0009-0008-4113-0641)
- Augustin Ruiz (ORCID: https://orcid.org/0000-0003-2633-2495)
- Michael Clark (ORCID: https://orcid.org/0000-0002-8006-4332)
- John Campos (ORCID: https://orcid.org/0000-0003-4213-0033)
- Paul Olsen (ORCID: https://orcid.org/0000-0001-8132-3722)
- Mitchell D. Kilgore (ORCID: https://orcid.org/0000-0003-1101-6924)
- Sarah Walling-Bell (ORCID: https://orcid.org/0000-0001-6995-2681)
- Lydia Ng (ORCID: https://orcid.org/0000-0002-7499-3514)
- Samuel T. Barlow (ORCID: https://orcid.org/0000-0002-2444-8876)
- Gonzalo E. Mena (ORCID: https://orcid.org/0000-0003-4432-9679)
- Windy Ho (ORCID: https://orcid.org/0000-0001-6200-9906)
- Zoe Maltzer (ORCID: https://orcid.org/0000-0002-0993-7604)
- Omar Kana (ORCID: https://orcid.org/0000-0002-7772-4694)
- Song‐Lin Ding (ORCID: https://orcid.org/0000-0002-7072-5272)
- David R. Haynor (ORCID: https://orcid.org/0000-0002-8940-7426)
- Ed S. Lein (ORCID: https://orcid.org/0000-0001-9012-6552)
- Eitan S Kaplan (ORCID: https://orcid.org/0000-0002-9355-324X)
- Luke Esposito (ORCID: https://orcid.org/0000-0002-3565-9126)
- Tom Egdorf
- Rachel Dalley (ORCID: https://orcid.org/0000-0001-7461-7845)
- Giuseppe-Antonio Saldi (ORCID: https://orcid.org/0000-0002-9994-7354)
- Michael Hawrylycz (ORCID: https://orcid.org/0000-0002-5741-8024)
- Sarah Khawand (ORCID: https://orcid.org/0009-0007-7399-6311)
- Mark Montine (ORCID: https://orcid.org/0009-0009-1090-9983)
- Maiya I Pacleb (ORCID: https://orcid.org/0009-0000-0242-2475)
- Brian Lee (ORCID: https://orcid.org/0000-0002-3210-5638)
- Nicholas Peña
- Matt Sullivan
- Yi Ding (ORCID: https://orcid.org/0009-0003-9515-8758)
- Eric B. Larson (ORCID: https://orcid.org/0000-0003-1108-6164)
- Rebecca Ferrer (ORCID: https://orcid.org/0000-0003-4775-1285)
- Kelly Meyers (ORCID: https://orcid.org/0000-0002-7631-1572)
- Angela Wilson (ORCID: https://orcid.org/0009-0000-4426-8349)
- Ming Xiao
- Christine L. Mac Donald
- Lisa M. Keene
Institutions
- Allen Institute for Brain Science (US)
- Kaiser Permanente Washington Health Research Institute (US)
- University of Washington (US)
- Chan Zuckerberg Initiative (United States) (US)
- Allen Institute (US)
- Neurological Surgery (US)
- Carnegie Mellon University (US)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2024-10-14
- DOI
- https://doi.org/10.1038/s41593-024-01774-5
- Citations
- 216
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 51.47
Funders
- National Institute on Aging