Evidence map›Paper›PMID 37985399›Full record

ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2024

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.

Yuan Hou, Jessica Z K Caldwell, Justin D Lathia, James B Leverenz, Andrew A Pieper, Jeffrey Cummings, Feixiong Cheng

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.

0numbers the graph read from it
0cells of the map it votes in
19citing papers in PubMed
2.3field-weighted citation impact, top 11% of its field
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

19 citing papers in PubMed, 19 citations in OpenAlex.

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  9. Single-cell landscape of sex-specific drivers of Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
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  16. Cell type-specific master metabolic regulators of Alzheimer's disease.bioRxiv : the preprint server for biology · 2025
    Article
  17. Review
  18. Review
  19. Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2024
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 5 institutions in 1 country.

Yuan HouGenomic Medicine Institute, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio, USA.
Jessica Z K CaldwellDepartment of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
Justin D LathiaDepartment of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
James B LeverenzLou Ruvo Center for Brain Health, Cleveland Clinic, Neurological Institute, Cleveland, Ohio, USA.
Andrew A PieperBrain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
Jeffrey CummingsChambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, Nevada, USA.
Feixiong ChengGenomic Medicine Institute, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio, USA.
Case Western Reserve University · USCleveland Clinic · USCleveland Clinic Lerner College of Medicine · USGeriatric Research Education and Clinical Center · USUniversity of Nevada, Las Vegas · US

Funding

Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
Project 4 - Mechanistic studies on the role of the gut microbiome in models for Alzheimer's diseaseU19AG063744 · NIA · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI ROB KNIGHT, Rima F Kaddurah-Daouk · 2019 to 2026
$54.1M
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
Trial-Ready Cohort for Preclinical/Prodromal Alzheimer's DiseaseR01AG053798 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI AISEN, PAUL S., CUMMINGS, JEFFREY L. · 2017 to 2022
$39.4M
Translational and Therapeutics CoreP30AG072959 · NIA · CLEVELAND CLINIC LERNER COM-CWRU · PI JAGAN AYYAPPAN PILLAI · 2021 to 2026
$23.9M
Renewal of Centers of Biomedical Research Excellence (COBRE) (Phase 2) CNTN - ResubmissionP20GM109025 · NIGMS · CLEVELAND CLINIC FOUNDATION · PI Robert J. Fox, Jefferson Kinney · 2015 to 2026
$22.8M
RISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4M
Chronic Traumatic Encephalopathy: Detection, Diagnosis, Course, and Risk FactorsU01NS093334 · NINDS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI CUMMINGS, JEFFREY L., REIMAN, ERIC MICHAEL · 2016 to 2022
$17.0M
Sex-specific differences in the tumor microenvironment alter glioblastoma growthP01CA245705 · NCI · CLEVELAND CLINIC LERNER COM-CWRU · PI Justin D. Lathia · 2020 to 2026
$15.0M
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
NCI NIH HHS P01 CA245705NIA NIH HHS K08 AG065463NIA NIH HHS P20 AG068053NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG072959NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG030146NIA NIH HHS R01 AG036836NIA NIH HHS R01 AG053798NIA NIH HHS R01 AG066707NIA NIH HHS R01 AG069901NIA NIH HHS R01 AG074392NIA NIH HHS R01 AG076448NIA NIH HHS R01 AG082118NIA NIH HHS R01 AG084250NIA NIH HHS R21 AG083003NIA NIH HHS R35 AG071476NIA NIH HHS R56 AG074001NIA NIH HHS RF1 AG082211NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG061356NIA NIH HHS U01 AG073323NIA NIH HHS U19 AG063744NIGMS NIH HHS P20 GM109025NINDS NIH HHS RF1 NS133812NINDS NIH HHS U01 NS093334
6 · The paper itself

Abstract

introductionThe molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood.

methodsTo address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort.

resultsWe identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism. DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. HIGHLIGHTS: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.

Indexed as

Alzheimer DiseaseEndophenotypesFemaleGlutamatesHumansMaleMicrogliaSex CharacteristicsGlutamatesAlzheimer's diseaseendophenotypeglutamateimmunometabolismmicrogliamulti-omicssex difference

Identifiers

PMID37985399
PMCPMC10916937
OpenAlexW4388851098

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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.