ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2026
Cellular transcriptomic signatures underpinning the heterogeneity of depression in Alzheimer's disease.
Michael W Lutz, Zhaohui Man, Ornit Chiba-Falek
Abstract read
In one paragraphArticle in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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2 · The registryThe trial behind it
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4 · The recordCorrections and comments
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5 · Who and what moneyAuthors and funding
3 authors.
Michael W LutzDivision of Translational Brain Sciences, Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA.
Zhaohui ManDivision of Translational Brain Sciences, Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA.
Ornit Chiba-FalekDivision of Translational Brain Sciences, Department of Neurology, Duke University School of Medicine, Durham, North Carolina, USA.
Funding
SUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1991 to 2020
$49.1MRISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4MMulti-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
$13.7MPathway 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
$13.6MAlzheimer 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
$8.5MDeconstructing 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
$4.0MDeciphering the regulation of gene expression in the etiology of LOADR01AG057522 · NIA · DUKE UNIVERSITY · PI CHIBA-FALEK, ORNIT, LUTZ, MICHAEL WILLIAM · 2017 to 2021
$3.6MElucidating 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
$3.3MExploring the Role of the Brain Transcriptome in Cognitive DeclineR01AG036836 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI DE JAGER, PHILIP L · 2011 to 2014
$2.9MUntangling the diversity in the genetic architecture of late-onset Alzheimer's disease using single cell multi-omicsRF1AG077695 · NIA · DUKE UNIVERSITY · PI CHIBA-FALEK, ORNIT · 2022 to 2022
$2.3MIdentifying, validating and targeting AD susceptibility networks in monocytesR01AG048015 · NIA · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI DE JAGER, PHILIP L · 2014 to 2018
$1.9MCognitive Decline and Dementia: Life Experiences and the Brain Histone EpigenomeRC2AG036547 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2009 to 2010
$998kAlzheimer's Association 22-AAIIA-953269National Institutes of Health/National Institute on Aging (NIH/NIA) R01 AG057522National Institutes of Health/National Institute on Aging (NIH/NIA) RF1 AG077695NIA NIH HHS P30 AG010161NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG036836NIA NIH HHS R01 AG048015NIA NIH HHS R01 AG057522NIA NIH HHS R01 AG066831NIA NIH HHS RC2 AG036547NIA NIH HHS RF1 AG057473NIA NIH HHS RF1 AG077695NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG061356NIA NIH HHS U01 AG072572
6 · The paper itselfAbstract
introductionLate-onset Alzheimer's disease (LOAD) and major depressive disorder (MDD) share genetic etiologies. Here, we investigated brain transcriptomic landscapes to gain insights into shared and divergent molecular and biological etiologies across LOAD and MDD.
methodsBrain single-nucleus RNA sequencing (snRNA-seq) datasets from cognitively normal older and young individuals and LOAD patients stratified by comorbid MDD were analyzed to identify differential expressed genes (DEGs). Using cell type-specific DEGs we performed biological pathway and intercellular-communication networks analyses. We investigated shared DEGs across MDD and LOAD cohorts and sex-specific DEGs. Results were validated by comparison with four transcriptomic and proteomic studies of MDD and depression.
resultsMDD-associated dysregulated genes and pathways were shared between LOAD and cognitive-normal individuals, including JUNB and DUSP1 in glutamatergic neurons, and PRAM1 and SNX9 in microglia. DEGs shared between the MDD and LOAD cohorts included HSPA1A and NDUFB7 in glutamatergic neurons. Sex interaction analysis identified numerous new DEGs in the MDD cohorts, whereas there were ≈5 to 10 times more DEGs in female than in male individuals. LOAD and MDD common microglial pathways included neuronal injury, stress, peroxisome proliferator-activated receptor (PPAR) signaling and interferon alpha/beta signaling. DISCUSSION: LOAD and MDD exhibited common molecular profiles, dysregulated pathways, and cellular communication changes. MDD develops earlier in life, thus, our findings provide a window into early molecular and biological processes preceding LOAD-onset.
Indexed as
Alzheimer DiseaseBrainMajor Depressive DisorderTranscriptomeAgedFemaleGene Expression ProfilingHumansMaleProteomicsAlzheimer's diseaseco‐pathologiesdisease heterogeneitydisease subtypesmajor depressive disordermultiomicsneuropsychiatric symptomssingle‐cell sequencingtranscriptomicstranslational science
Identifiers
PMID42728740
PMCPMC13569991
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