Evidence map›Paper›PMID 40393985›Full record

ArticleNature communications2025

An integrative systems-biology approach defines mechanisms of Alzheimer's disease neurodegeneration.

Matthew J Leventhal, Camila A Zanella, Byunguk Kang, Jiajie Peng, David Gritsch, Zhixiang Liao, Hassan Bukhari, Tao Wang, Ping-Chieh Pao, Serwah Danquah and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing 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

15 citing papers in PubMed.

  1. Review
  2. Review
  3. Review
  4. Review
  5. Neurodegenerative Diseases in Children: A Comprehensive Review.International journal of molecular sciences · 2026
    Review
  6. Article
  7. Article
  8. Article
  9. Review
  10. Article
  11. Article
  12. Article
  13. Article
  14. Review
  15. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors.

Matthew J LeventhalMIT Ph.D. Program in Computational and Systems Biology, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-5995-5202
Camila A ZanellaDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-2448-5765
Byunguk KangDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.ORCID http://orcid.org/0009-0004-5540-7745
Jiajie PengPrecision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.ORCID http://orcid.org/0000-0002-3857-7927
David GritschPrecision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.
Zhixiang LiaoPrecision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.ORCID http://orcid.org/0000-0001-7014-5465
Hassan BukhariDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Tao WangPrecision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.ORCID http://orcid.org/0000-0002-5728-6463
Ping-Chieh PaoPicower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.ORCID http://orcid.org/0000-0001-6788-7185
Serwah DanquahSpatial Technology Platform, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Joseph BenetatosDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Ralda NehmeSpatial Technology Platform, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-7215-3311
Samouil FarhiSpatial Technology Platform, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1359-4568
Li-Huei TsaiBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1262-0592
Xianjun DongPrecision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.
Clemens R ScherzerPrecision Neurology Program, Brigham and Women's Hospital and Harvard Medical school, Boston, MA, USA.
Mel B FeanyDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0315-7970
Ernest FraenkelMIT Ph.D. Program in Computational and Systems Biology, Cambridge, MA, USA. fraenkel-admin@mit.edu.ORCID http://orcid.org/0000-0001-9249-8181

Funding

Vascular Structure and Function in Cognitive AgingP01AG003949 · NIA · YESHIVA UNIVERSITY · PI Richard B. LIPTON · 1985 to 2026
$73.9M
Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
Procurement and Characterization of Postmortem Brain TissueZICMH002903 · NIMH · NATIONAL INSTITUTE OF MENTAL HEALTH · PI MARENCO, STEFANO · 2009 to 2025
$56.0M
SUPPLEMENT TO ALZHEIMERS DISEASE PATIENT REGISTRYU01AG006786 · NIA · MAYO CLINIC ROCHESTER · PI GRAFF-RADFORD, JONATHAN, JACK, CLIFFORD R. · 1986 to 2023
$49.6M
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
VESICULAR LOCALIZATION AND FUNCTION OF PRESENILIN 1 FRAGMENTP50AG005138 · NIA · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI GROSSMAN, HILLEL · 1985 to 2019
$37.9M
THE PGRN/TDP-43 AXIS IN ALZHEIMER?S DISEASE AND NEURODEGENERATIONP50AG016574 · NIA · MAYO CLINIC ROCHESTER · PI PETERSEN, RONALD C · 1999 to 2018
$36.9M
Research Education ComponentP30AG019610 · NIA · SUN HEALTH RESEARCH INSTITUTE · PI REIMAN, ERIC MICHAEL · 2001 to 2020
$32.5M
Integrating the exposome and methylome to inform brain molecular changes in ADRD across established diverse cohorts.U01AG046139 · NIA · UNIVERSITY OF FLORIDA · PI ERTEKIN-TANER, NILUFER, FUNK, CORY · 2013 to 2022
$24.6M
RISK FACTORS, PATHOLOGY, AND CLINICAL EXPRESSIONS OF ADR01AG015819 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 1998 to 2024
$21.4M
QUANTITATIVE ANALYSIS OF MICROVASCULAR CHANGES IN THE AGING BRAINP01AG002219 · NIA · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI HAROUTUNIAN, VAHRAM · 1985 to 2009
$19.2M
Intramural NIH HHS ZIC MH002903NIA NIH HHS P01 AG002219NIA NIH HHS P01 AG003949NIA NIH HHS P01 AG017216NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG019610NIA NIH HHS P50 AG005138NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG025711NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG018023NIA NIH HHS R01 AG032990NIA NIH HHS R01 AG036836NIA NIH HHS RF1 AG057331NIA NIH HHS RF1 AG075901NIA NIH HHS RF1 AG076214NIA NIH HHS U01 AG006786NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG061356NIDA NIH HHS HHSN271201300031CNIGMS NIH HHS T32 GM087237NIH HHS P40 OD018537NIH HHS R24 OD030002NIMH NIH HHS P50 MH066392NIMH NIH HHS P50 MH084053NIMH NIH HHS R01 MH075916NIMH NIH HHS R01 MH080405NIMH NIH HHS R01 MH085542NIMH NIH HHS R01 MH093725NIMH NIH HHS R01 MH097276NIMH NIH HHS R01 MH109677NIMH NIH HHS R01 MH109897NIMH NIH HHS R01 MH110921NIMH NIH HHS R37 MH057881NIMH NIH HHS U01 MH103392NIMH NIH HHS U01 MH116442NINDS NIH HHS R01 NS080820NINDS NIH HHS R35 NS132225NINDS NIH HHS U24 NS072026U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01-AG057331
6 · The paper itself

Abstract

Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer's disease, remain incompletely understood. To define relevant pathways, we conducted an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila. We also measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer's disease and identified Alzheimer's genetic variants that modify gene expression in disease-vulnerable neurons in humans. We then used a network model to integrate these data with previously published Alzheimer's disease proteomics, lipidomics and genomics. Here, we computationally predict and experimentally confirm how HNRNPA2B1 and MEPCE enhance toxicity of the tau protein, a pathological feature of Alzheimer's disease. Furthermore, we demonstrated that the screen hits CSNK2A1 and NOTCH1 regulate DNA damage in Drosophila and human stem cell-derived neural progenitor cells. Our study identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer's disease.

Indexed as

Alzheimer DiseaseNerve DegenerationSystems BiologyAnimalsDisease Models, AnimalDNA DamageDrosophilaDrosophila melanogasterDrosophila ProteinsHumansMetabolomicsNeuronsProteomicsReceptor, Notch1tau ProteinsDrosophila ProteinsReceptor, Notch1tau Proteins

Identifiers

PMID40393985
PMCPMC12092734

What OpenQuestion holds

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Read underepoch 390

Registered trials

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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.