Evidence map›Paper›PMID 41035073›Full record

ArticleMolecular neurodegeneration2025

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease.

Isabel Castanho, Pourya Naderi Yeganeh, Carles A Boix, Sarah L Morgan, Hansruedi Mathys, Dmitry Prokopenko, Bartholomew White, Larisa M Soto, Giulia Pegoraro, Saloni Shah and 10 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular neurodegeneration, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing 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

11 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Stable neuronal representations underlie cognitive resilience to Alzheimer's disease pathology.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Article
  5. Article
  6. Single-cell transcriptomic analysis reveals APOE genotype-dependent sex differences in Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Article
  7. Article
  8. Review
  9. Article
  10. Review
  11. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

20 authors.

Isabel Castanho *Harvard Medical School, Boston, MA, USA.ORCID 0000-0003-1413-626X
Pourya Naderi Yeganeh *Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-4693-8331
Carles A BoixComputer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, USA.ORCID 0000-0001-9212-856X
Sarah L MorganHarvard Medical School, Boston, MA, USA.
Hansruedi MathysUniversity of Pittsburgh Brain Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Dmitry ProkopenkoHarvard Medical School, Boston, MA, USA.
Bartholomew WhiteHarvard Medical School, Boston, MA, USA.
Larisa M SotoHarvard Medical School, Boston, MA, USA.
Giulia PegoraroHarvard Medical School, Boston, MA, USA.
Saloni ShahHarvard Medical School, Boston, MA, USA.
Athanasios PloumakisHarvard Medical School, Boston, MA, USA.
Nikolas KalavrosHarvard Medical School, Boston, MA, USA.
David A BennettRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Christoph LangeDepartment of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Doo Yeon KimHarvard Medical School, Boston, MA, USA.
Lars BertramLübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Lübeck, Germany.
Li-Huei TsaiBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Manolis KellisComputer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, USA.
Rudolph E TanziHarvard Medical School, Boston, MA, USA. rtanzi@mgh.harvard.edu.
Winston HideHarvard Medical School, Boston, MA, USA. whide@bidmc.harvard.edu.ORCID 0000-0002-8621-3271

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
Rush Alzheimer's Disease Research CenterP30AG072975 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI Lisa L Barnes, Julie A. Schneider · 2021 to 2026
$24.7M
Resilience/Resistance to Alzheimer's Disease in Centenarians and Offspring (RADCO)U19AG073172 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI KIM, DOO YEON · 2021 to 2025
$23.1M
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
Epigenomic, transcriptional and cellular dissection of Alzheimer's variantsR01AG058002 · NIA · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI HYMAN, BRADLEY T., JAENISCH, RUDOLF · 2017 to 2021
$7.9M
Elucidating the Molecular Mechanisms of Neuropsychiatric Symptoms in Alzheimer's DiseaseR01AG062335 · NIA · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI KELLIS, MANOLIS, TSAI, LI-HUEI · 2018 to 2022
$6.5M
Role of the g-secretase/PS1 complex in APP processingR01AG014713 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI KIM, DOO YEON · 1997 to 2018
$5.9M
Single-cell epigenomic and trancriptional dissection of sex-specific differences in Alzheimer’s DiseaseR01AG074003 · NIA · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI KELLIS, MANOLIS, TSAI, LI-HUEI · 2021 to 2025
$5.4M
Single-cell transcriptional and epigenomic dissection of Alzheimer's Disease and Related DementiasU01NS110453 · NINDS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI KELLIS, MANOLIS, TSAI, LI-HUEI · 2018 to 2020
$4.0M
Alzheimer's Association AARF-23-1148927NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG072975NIA NIH HHS P30AG10161NIA NIH HHS P30AG72975NIA NIH HHS R01 AG014713NIA NIH HHS R01AG014713NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01AG048080NIA NIH HHS R01AG054012NIA NIH HHS R01 AG058002NIA NIH HHS R01AG058002NIA NIH HHS R01 AG062335NIA NIH HHS R01AG062335NIA NIH HHS R01 AG062547NIA NIH HHS R01AG062547NIA NIH HHS R01 AG074003NIA NIH HHS R01AG074003NIA NIH HHS R01 AG081017NIA NIH HHS R01AG081017NIA NIH HHS R01 AG082093NIA NIH HHS R01AG082093NIA NIH HHS R01AG15819NIA NIH HHS R01AG17917NIA NIH HHS RF1 AG048080NIA NIH HHS RF1 AG054012NIA NIH HHS RF1 AG054321NIA NIH HHS RF1AG054321NIA NIH HHS RF1 AG062377NIA NIH HHS RF1AG062377NIA NIH HHS RF1 AG085291NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG061356NIA NIH HHS U01AG46152NIA NIH HHS U01AG61356NIA NIH HHS U01NS110453NIA NIH HHS U19 AG073172NIA NIH HHS U19AG073172NINDS NIH HHS U01 NS110453
6 · The paper itself

Abstract

backgroundA significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD.

methodsThis study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition.

resultsTranscriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2C

conclusionsWe have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Indexed as

Alzheimer DiseaseBrainNeuronsAgedAged, 80 and overFemaleHumansKruppel-Like Factor 4MaleTranscriptomeKLF4 protein, humanKruppel-Like Factor 4Alzheimer’s diseaseCognitive reserveCognitive resilienceE/I imbalanceGene expressionGeneticsRare variantsSingle-cell RNA sequencingSST interneuronsTranscriptomicsVulnerability

Identifiers

PMID41035073
PMCPMC12487324

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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.