ArticleNeuron2020
Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways.
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Article in Neuron, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 145 papers.
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145citing papers in PubMed
17.5field-weighted citation impact, top 1% of its field
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Who cites it
145 citing papers in PubMed, 251 citations in OpenAlex.
- An aging-sensitive secreted phospholipase confers neuroprotection and cognitive resilience.Nature neuroscience · 2026Article
- Global and regional amyloid-β in explaining APOE-ε4 and sex associations with medial temporal tau: a neuropathology study.Acta neuropathologica · 2026Article
- Associations between serum estradiol and estrone and Alzheimer's disease biomarkers: An analysis in female participants from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS).Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Novel Plasma Proteins Associated With Alzheimer's Disease Risk in APOE ε4 Carriers and Non-carriers.Research square · 2026Article
- Article
- Amino acid and appendicular skeletal muscle mass insufficiency are associated to cognitive decline in Chinese population.GeroScience · 2026Article
- Dose- and state-dependent enhancement of hippocampal CA1 pyramidal neuron excitability by GM1 ganglioside in male rats with cholinergic lesions.Scientific reports · 2026Article
- HDL-mimetic peptide treatment reverses APOE4-induced transcriptomic and lipidomic alterations in the brain of humanized APOE mice.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Spatial-temporal lipidomics reveals dysregulated lipid metabolism in mouse brain during Alzheimer's disease progression.Journal of advanced research · 2026Article
- Molecular characterization of humanized APOE mouse models reveals source and genotype dependent differences.Molecular neurodegeneration · 2026Article
- The apolipoprotein gene: a modulating role on brain volume and cognitive function in carriers of the fragile X premutation.Neurobiology of disease · 2026Article
- C16-siRNAs in Focus: Development of ALN-APP, a Promising RNAi-Based Therapeutic for Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- SerpinA3N-APOE interaction in astrocytes exacerbates Alzheimer's disease progression through NFκB activation.Journal of neuroinflammation · 2025Article
- APOE4 to APOE2 allelic switching in mice improves Alzheimer's disease-related metabolic signatures, neuropathology and cognition.Nature neuroscience · 2025Article
- Inflammation associated microglial expansion disrupts hippocampal glial network communication, driving postoperative neurocognitive impairment.Journal of neuroinflammation · 2025Article
- Roles of TREM2 in Alzheimer's disease.Translational neurodegeneration · 2025Review
- Aging, Rather than Genotype, Is the Principal Contributor to Differential Gene Expression Within Targeted Replacement APOE2, APOE3, and APOE4 Mouse Brain.Brain sciences · 2025Article
- APOE genotype influences on the brain metabolome of aging mice - role for mitochondrial energetics in mechanisms of resilience in APOE2 genotype.Molecular neurodegeneration · 2025Article
- Emerging Role of Oligodendrocytes Malfunction in the Progression of Alzheimer's Disease.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2025Review
- Monitoring the Dynamics of Alzheimer's Disease Biomarkers and the APOE-Tau Axis via Human Cerebral Organoids with Immuno-SERS.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
85 more citing papers are in PubMed but not listed here.
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Authors and funding
32 authors at 4 institutions in 2 countries.
Na ZhaoDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: zhao.na@mayo.edu.
Yingxue RenDepartment of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA.
Yu YamazakiDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Wenhui QiaoDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Fuyao LiDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Lindsey M FeltonDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Siamak MahmoudiandehkordiDepartment of Psychiatry and Behavioral Sciences, Department of Medicine and the Duke Institute for Brain Sciences, Duke University, Durham, NC 27708, USA.
Alexandra Kueider-PaisleyDepartment of Psychiatry and Behavioral Sciences, Department of Medicine and the Duke Institute for Brain Sciences, Duke University, Durham, NC 27708, USA.
Berkiye SonoustounDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Matthias ArnoldDepartment of Psychiatry and Behavioral Sciences, Department of Medicine and the Duke Institute for Brain Sciences, Duke University, Durham, NC 27708, USA; Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria 85764, Germany.
Francis ShueNeuroscience Graduate Program, Mayo Clinic, Jacksonville, FL 32224, USA.
Jiaying ZhengNeuroscience Graduate Program, Mayo Clinic, Jacksonville, FL 32224, USA.
Olivia N AttrebiDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Yuka A MartensDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Zonghua LiDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Ligia BasteaDepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
Axel D MenesesDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Kai ChenDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
J Will ThompsonDuke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27701, USA.
Lisa St John-WilliamsDuke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.
Masaya TachibanaDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Tomonori AikawaDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Hiroshi OueDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Lucy JobDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Akari YamazakiDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Chia-Chen LiuDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Peter StorzDepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
Yan W AsmannDepartment of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA.
Nilüfer Ertekin-TanerDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
Takahisa KanekiyoDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Rima Kaddurah-DaoukDepartment of Psychiatry and Behavioral Sciences, Department of Medicine and the Duke Institute for Brain Sciences, Duke University, Durham, NC 27708, USA.
Guojun BuDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Neuroscience Graduate Program, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: bu.guojun@mayo.edu.
Mayo Clinic in Florida · USDuke University · USHelmholtz Zentrum München · DEJacksonville College · US
Funding
Vascular Structure and Function in Cognitive AgingP01AG003949 · NIA · YESHIVA UNIVERSITY · PI Jelena Pavlovic · 1985 to 2026
$73.9MSUPPLEMENT TO ALZHEIMERS DISEASE PATIENT REGISTRYU01AG006786 · NIA · MAYO CLINIC ROCHESTER · PI GRAFF-RADFORD, JONATHAN, JACK, CLIFFORD R. · 1986 to 2023
$49.6MSUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1991 to 2020
$49.1MEPIDEMIOLOGY OF NEURAL RESERVE AND NEUROBIOLOGY IN AGINGR01AG017917 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2001 to 2023
$43.3MTHE PGRN/TDP-43 AXIS IN ALZHEIMER?S DISEASE AND NEURODEGENERATIONP50AG016574 · NIA · MAYO CLINIC ROCHESTER · PI BU, GUOJUN · 1999 to 2018
$36.9MResearch Education ComponentP30AG019610 · NIA · SUN HEALTH RESEARCH INSTITUTE · PI GONZALEZ HERNANDEZ, GRACIELA · 2001 to 2020
$32.5MIntegrating the exposome and methylome to inform brain molecular changes in ADRD across established diverse cohorts.U01AG046139 · NIA · UNIVERSITY OF FLORIDA · PI ERTEKIN-TANER, NILUFER, PETERS, METTE · 2013 to 2022
$24.6MRISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4MViral Vectors CoreP01NS074969 · NINDS · WASHINGTON UNIVERSITY · PI SNIDER, BARBARA JOY · 2012 to 2021
$13.0MTRANSGENIC MODELING OF TAUOPATHYP01AG017216 · NIA · MAYO CLINIC JACKSONVILLE · PI DICKSON, DENNIS WILLIAM · 1999 to 2011
$12.0MMetabolomic Signatures for Disease Sub-classification and Target Prioritization in AMP-ADU01AG061359 · NIA · DUKE UNIVERSITY · PI KADDURAH-DAOUK, RIMA F, KASTENMULLER, GABI · 2018 to 2022
$10.0MIntegrative translational discovery of vascular risk factors in aging and dementiaRF1AG051504 · NIA · MAYO CLINIC JACKSONVILLE · PI BU, GUOJUN, ERTEKIN-TANER, NILUFER · 2015 to 2019
$9.8MNCI NIH HHS R01 CA200572NIA NIH HHS F31 AG051356NIA NIH HHS P01 AG003949NIA NIH HHS P01 AG017216NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG019610NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG025711NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG018023NIA NIH HHS R01 AG027924NIA NIH HHS R01 AG032990NIA NIH HHS R01 AG035355NIA NIH HHS R01 AG046171NIA NIH HHS R01 AG061796NIA NIH HHS R01 AG066395NIA NIH HHS R21 AG052423NIA NIH HHS R37 AG027924NIA NIH HHS RF1 AG046205NIA NIH HHS RF1 AG051504NIA NIH HHS RF1 AG051550NIA NIH HHS RF1 AG056130NIA NIH HHS RF1 AG057181NIA NIH HHS RF1 AG062110NIA NIH HHS U01 AG006786NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG061359NINDS NIH HHS P01 NS074969NINDS NIH HHS R01 NS080820NINDS NIH HHS U24 NS072026
Abstract
Evidence suggests interplay among the three major risk factors for Alzheimer's disease (AD): age, APOE genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes. Importantly, these networks and gene expression changes were mostly conserved in human brains. Finally, we observed a significant interaction between age, APOE genotype, and sex on unfolded protein response pathway. In the periphery, APOE2 drove distinct blood metabolome profile highlighted by the upregulation of lipid metabolites. Our work identifies unique and interactive molecular pathways underlying AD risk factors providing valuable resources for discovery and validation research in model systems and humans.
Indexed as
Adaptor Proteins, Signal TransducingAge FactorsAgingAlzheimer DiseaseAnimalsApolipoprotein E2Apolipoprotein E3Apolipoprotein E4Apolipoproteins EBrainFemaleGene ExpressionGene Expression ProfilingGene Regulatory NetworksGenotypeHumansAdaptor Proteins, Signal TransducingApoE protein, humanApolipoprotein E2Apolipoprotein E3Apolipoprotein E4Apolipoproteins EMembrane GlycoproteinsMembrane ProteinsReceptors, ImmunologicSerpinsTREM2 protein, humanTYROBP protein, humanageAlzheimer’s diseaseAPOEextracellular vesiclesinflammationlipid metabolismmetabolomicsSerpina3sextranscriptomics
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