Evidence map›Paper›PMID 41456076›Full record

ArticleAlzheimer's research & therapy2025

Exploring cellular heterogeneity: single-cell and spatial transcriptomics of Alzheimer's disease brains and iPSC-derived microglia.

Anjali Garg, Sheeny Vo, Iara D De Souza, Ayslan Castro Brant, Logan Brase, Ekaterina Aladyeva, Ricardo D 'o Albanus, Aasritha Nallapu, Hongjun Fu, Oscar Harari

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's research & therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

  1. Review
  2. Review
  3. Review
  4. Article
  5. Review
  6. Review
  7. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors.

Anjali GargDepartment of Psychiatry, Washington University, Saint Louis, St. Louis, MO, USA.
Sheeny Vo *Department of Neuroscience, OSU Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
Iara D De Souza *Department of Neurology, Division of Neurogenetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Ayslan Castro BrantDepartment of Neurology, Division of Neurogenetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Logan BraseDepartment of Psychiatry, Washington University, Saint Louis, St. Louis, MO, USA.
Ekaterina AladyevaDepartment of Psychiatry, Washington University, Saint Louis, St. Louis, MO, USA.
Ricardo D 'o AlbanusDepartment of Psychiatry, Washington University, Saint Louis, St. Louis, MO, USA.
Aasritha NallapuDepartment of Psychiatry, Washington University, Saint Louis, St. Louis, MO, USA.
Hongjun FuDepartment of Neuroscience, OSU Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
Oscar HarariDepartment of Psychiatry, Washington University, Saint Louis, St. Louis, MO, USA. oscar.harari@osumc.edu.

Funding

SUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1991 to 2020
$49.1M
EPIDEMIOLOGY OF NEURAL RESERVE AND NEUROBIOLOGY IN AGINGR01AG017917 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2001 to 2023
$43.3M
RISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4M
Multi-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targetsU01AG061356 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2018 to 2022
$13.7M
Pathway discovery, validation and compound identification for Alzheimer's disease - SupplementU01AG046152 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2013 to 2017
$13.6M
Investigating the Functional Impact of AD Risk Genes on Neuro-Vascular InteractionsU01AG072464 · NIA · REGENERATIVE RESEARCH FOUNDATION · PI HARARI, OSCAR, KAMPMANN, MARTIN · 2021 to 2025
$8.7M
Alzheimer variants: Propagation of shared functional changes across cellular networksU01AG072572 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI DE JAGER, PHILIP L, ST GEORGE-HYSLOP, PETER HENRY · 2021 to 2025
$8.5M
Genetic Epidemiology of Cognitive Decline in an Aging Population SampleR01AG030146 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI EVANS, DENIS A · 2007 to 2018
$6.2M
MENDELIAN RANDOMIZATION FOR UNBIAS BIOMARKER DISCOVERY FOR AD AND OTHER COMPLEX TRAITSR01AG057777 · NIA · WASHINGTON UNIVERSITY · PI HARARI, OSCAR · 2018 to 2022
$4.1M
Deconstructing and modeling the single cell architecture of the Alzheimer brainRF1AG057473 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI BENNETT, DAVID ALAN, DE JAGER, PHILIP L · 2017 to 2018
$4.0M
Elucidating changes in astrocyte subpopulations associated with resistance to Alzheimers Disease pathology in multi-ethnic cohortsR01AG066831 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI MENON, VILAS · 2020 to 2024
$3.3M
Ectodermal-neural cortex 1 and neuronal vulnerability to tau pathology in Alzheimer's diseaseR01AG075092 · NIA · OHIO STATE UNIVERSITY · PI Hongjun Fu · 2022 to 2026
$2.4M
NIA NIH HHS P30 AG010161NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG030146NIA NIH HHS R01 AG057777NIA NIH HHS R01 AG066831NIA NIH HHS R01 AG075092NIA NIH HHS R56 AG067764NIA NIH HHS RF1 AG057473NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG061356NIA NIH HHS U01 AG072464NIA NIH HHS U01 AG072572NIH HHS R01AG057777, R56AG067764, U01AG072464, R01AG074012893NIH HHS R01AG075092
6 · The paper itself

Abstract

backgroundMicroglia, the brain’s resident immune cells, play a pivotal role in Alzheimer’s disease (AD) pathogenesis. These cells exhibit diverse transcriptional states in response to neuroinflammatory stimuli, and characterizing these states is essential for understanding AD mechanisms.

methodsWe integrated single-cell and spatial transcriptomic datasets from multiple cohorts and brain regions, encompassing both experimental models and human tissues. Findings were validated through immunostaining of human brain samples.

resultsOur comprehensive atlas revealed pronounced heterogeneity among microglial states, with disease-associated microglia (DAM) significantly enriched in AD brains compared to controls. Spatial transcriptomics and immunohistochemistry demonstrated that DAM predominantly localize to external cortical layers and near amyloid plaques, whereas homeostatic microglia are more abundant in internal cortical layers and distal regions. Immunofluorescence staining for P2RY12 and CD68 confirmed these spatial distributions.

conclusionBy harmonizing single-cell and spatial transcriptomics, we provide a detailed atlas of microglial diversity, highlighting regional and pathological specificity of microglial states in AD. SIGNIFICANCE: This work advances prior studies by mapping microglial transcriptional states across multiple human cohorts and experimental contexts, integrating spatial data to reveal novel anatomical patterns. The enrichment of DAM in external cortical layers and homeostatic microglia in internal layers represents a previously unreported finding with potential therapeutic implications. While not exhaustive of all microglial datasets, this study establishes the first integrated reference combining single-nucleus and spatial transcriptomics, underscoring the importance of linking microglial diversity to AD neuropathology and brain architecture.

Indexed as

Alzheimer DiseaseBrainMicrogliaTranscriptomeAnimalsHumansSingle-Cell AnalysisSingle-Cell Gene Expression AnalysisSpatial TranscriptomicsAlzheimer’s diseaseAmyloid betaImmunofluorescence stainingIntegrationMicrogliaSingle-nucleus RNA-seqSpatially resolved transcriptomicsTau

Identifiers

PMID41456076
PMCPMC12859894

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.