Multiregional single-cell profiling reveals shared and specialized cellular vulnerability in Alzheimer’s disease
10 affiliations
- 1Allen Institute, Brain Health, Seattle, WA
- 2Department of Statistics, University of Washington, Seattle, WA
- 3Allen Institute, Center for Data-Driven Discovery, Seattle, WA
- 4Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA
- 5Allen Institute, Brain Science, Seattle, WA
- 6Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA
- 7Kaiser Permanente Washington Health Research Institute, Seattle, WA
- 8Deep Science Ventures, United Kingdom, CM4 9DW
- 9Department of Radiology, University of Washington, Seattle, WA
- 10Department of Physiology and Biophysics, University of Washington, Seattle, WA
Abstract
Alzheimer’s disease (AD) is defined and staged by the stereotyped, progressive accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau (pTau) tangles across brain regions. These regions differ substantially in their architecture and function but share largely conserved cellular composition, with some regional specialization. As pathology accumulates, specific neurons are lost and non-neuronal cells shift toward disease-associated states, but whether the cell types affected in any one region are the same across the others has remained unclear. Here we extended the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD) to ten neo- and allocortical regions spanning the cortical arc of canonical AD staging, profiling approximately seven million nuclei from 84 donors with single-nucleus RNA-seq, ATAC-seq, and Multiome alongside quantitative neuropathology and whole-genome sequencing. Nuclei were mapped to an expanded BRAIN Initiative reference taxonomy of 207 cell types, and a hierarchical pseudo-progression framework derived continuous, donor-level measures of AD pathological burden within each region and across the brain by jointly modeling Aβ and pTau. Cellular changes were both highly selective and strikingly consistent: only ∼30% of cell types shifted in relative abundance, but those that did changed in a coherent direction across regions. Specific subsets of Sst, Lamp5, Vip, Sncg, and Pvalb inhibitory interneurons and myelinating oligodendrocytes were lost earliest in preclinical donors with minimal pathology, alongside initial emergence of AD-associated microglia; loss of L2/3 and selected deep-layer excitatory types, sharper microglial increases, and reactive astrocyte emergence followed in later-stage donors. Regionally specialized populations were also vulnerable, including expected allocortical types and, unexpectedly, primary visual cortex (V1C)-specialized layer 4 (L4 IT) excitatory neurons and intermixed Sst and Pvalb interneurons. Key changes replicated across three independent cohorts encompassing over 700 additional donors. We examined two complementary vulnerable populations in mechanistic detail: regionally specialized V1C L4 IT neurons lost late despite being widely considered resilient, and pan-cortical Sst interneurons lost earliest in disease. Applying a multi-agentic AI workflow that constructed literature-grounded hypotheses from differential expression to L4 IT neurons nominated hyperexcitability, mediated in part by high NMDA receptor expression, as a convergent vulnerability phenotype. Vulnerable Sst interneurons converged on hyperexcitability through partly distinct pathways, and were enriched for expression of AD GWAS-prioritized genes, linking their vulnerability to the genetic architecture of AD. These data, available at SEA-AD.org, provide a multiregional framework for the community to explore the molecular and cellular changes of AD progression.
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BibTeX
@misc{travaglini2026multiregional,
title = {{Multiregional single-cell profiling reveals shared and specialized cellular vulnerability in Alzheimer’s disease}},
author = {Kyle J. Travaglini and Mariano I. Gabitto and Yi Ding and Anamika Agrawal and Nadia O. Postupna and Joseph T. Mahoney and Eitan S Kaplan and Erica J. Melief and Jeff Goldy and Anish Bhaswanth Chakka and Ming Xiao and Tejas S Bajwa and Andreas Tjärnberg and Jeanelle Ariza and Song‐Lin Ding and Emily C. Gelfand and Omar Z. Kana and Hsin-Yu Lai and Brian Long and Victoria M. Rachleff and Giuseppe-Antonio Saldi and Caleb P. Schultz and Lauren Alfiler and Angela P. Ayala and Stuard Barta and Darren Bertagnolli and Trangthanh Pham and Tamara Casper and Rushil Chakrabarty and Michael Clark and Nasmil Valera Cuevas and Michael S. Cuoco and Rachel A. Dalley and Nick Dee and Laramie E. Duncan and Christina Kouskouti and Rebecca Ferrer and Lynn E. Fleckenstein and Jessica Gloe and Nathan Guilford and Junitta Guzman and Mark Hammond and Sam Hastings and David R. Haynor and Heino Hulsey-Vincent and Windy Ho and K. James and Zoe Juneau and Brian E. Kalmbach and Madhav Kannan and Moustafa Khedr and Christine Kim and Brian Lee and Naomi X. Martin and Rachel McCue and Delissa McMillen and Lisa Marie Milchsack and Francesco Moramarco and Beagan Nguy and Julie K. Nyhus},
howpublished = {bioRxiv (Cold Spring Harbor Laboratory)},
year = {2026},
month = jul,
doi = {10.64898/2026.07.01.734821},
url = {https://doi.org/10.64898/2026.07.01.734821},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Multiregional single-cell profiling reveals shared and specialized cellular vulnerability in Alzheimer’s disease
AU - Kyle J. Travaglini
AU - Mariano I. Gabitto
AU - Yi Ding
AU - Anamika Agrawal
AU - Nadia O. Postupna
AU - Joseph T. Mahoney
AU - Eitan S Kaplan
AU - Erica J. Melief
AU - Jeff Goldy
AU - Anish Bhaswanth Chakka
AU - Ming Xiao
AU - Tejas S Bajwa
AU - Andreas Tjärnberg
AU - Jeanelle Ariza
AU - Song‐Lin Ding
AU - Emily C. Gelfand
AU - Omar Z. Kana
AU - Hsin-Yu Lai
AU - Brian Long
AU - Victoria M. Rachleff
AU - Giuseppe-Antonio Saldi
AU - Caleb P. Schultz
AU - Lauren Alfiler
AU - Angela P. Ayala
AU - Stuard Barta
AU - Darren Bertagnolli
AU - Trangthanh Pham
AU - Tamara Casper
AU - Rushil Chakrabarty
AU - Michael Clark
AU - Nasmil Valera Cuevas
AU - Michael S. Cuoco
AU - Rachel A. Dalley
AU - Nick Dee
AU - Laramie E. Duncan
AU - Christina Kouskouti
AU - Rebecca Ferrer
AU - Lynn E. Fleckenstein
AU - Jessica Gloe
AU - Nathan Guilford
AU - Junitta Guzman
AU - Mark Hammond
AU - Sam Hastings
AU - David R. Haynor
AU - Heino Hulsey-Vincent
AU - Windy Ho
AU - K. James
AU - Zoe Juneau
AU - Brian E. Kalmbach
AU - Madhav Kannan
AU - Moustafa Khedr
AU - Christine Kim
AU - Brian Lee
AU - Naomi X. Martin
AU - Rachel McCue
AU - Delissa McMillen
AU - Lisa Marie Milchsack
AU - Francesco Moramarco
AU - Beagan Nguy
AU - Julie K. Nyhus
PY - 2026
DA - 2026/07/02
PB - bioRxiv (Cold Spring Harbor Laboratory)
DO - 10.64898/2026.07.01.734821
UR - https://doi.org/10.64898/2026.07.01.734821
AB - Alzheimer’s disease (AD) is defined and staged by the stereotyped, progressive accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated tau (pTau) tangles across brain regions. These regions differ substantially in their architecture and function but share largely conserved cellular composition, with some regional specialization. As pathology accumulates, specific neurons are lost and non-neuronal cells shift toward disease-associated states, but whether the cell types affected in any one region are the same across the others has remained unclear. Here we extended the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD) to ten neo- and allocortical regions spanning the cortical arc of canonical AD staging, profiling approximately seven million nuclei from 84 donors with single-nucleus RNA-seq, ATAC-seq, and Multiome alongside quantitative neuropathology and whole-genome sequencing. Nuclei were mapped to an expanded BRAIN Initiative reference taxonomy of 207 cell types, and a hierarchical pseudo-progression framework derived continuous, donor-level measures of AD pathological burden within each region and across the brain by jointly modeling Aβ and pTau. Cellular changes were both highly selective and strikingly consistent: only ∼30% of cell types shifted in relative abundance, but those that did changed in a coherent direction across regions. Specific subsets of Sst, Lamp5, Vip, Sncg, and Pvalb inhibitory interneurons and myelinating oligodendrocytes were lost earliest in preclinical donors with minimal pathology, alongside initial emergence of AD-associated microglia; loss of L2/3 and selected deep-layer excitatory types, sharper microglial increases, and reactive astrocyte emergence followed in later-stage donors. Regionally specialized populations were also vulnerable, including expected allocortical types and, unexpectedly, primary visual cortex (V1C)-specialized layer 4 (L4 IT) excitatory neurons and intermixed Sst and Pvalb interneurons. Key changes replicated across three independent cohorts encompassing over 700 additional donors. We examined two complementary vulnerable populations in mechanistic detail: regionally specialized V1C L4 IT neurons lost late despite being widely considered resilient, and pan-cortical Sst interneurons lost earliest in disease. Applying a multi-agentic AI workflow that constructed literature-grounded hypotheses from differential expression to L4 IT neurons nominated hyperexcitability, mediated in part by high NMDA receptor expression, as a convergent vulnerability phenotype. Vulnerable Sst interneurons converged on hyperexcitability through partly distinct pathways, and were enriched for expression of AD GWAS-prioritized genes, linking their vulnerability to the genetic architecture of AD. These data, available at SEA-AD.org, provide a multiregional framework for the community to explore the molecular and cellular changes of AD progression.
ER -