Evidence map›Paper›PMID 40135662›Full record

ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025

Pathways underlying selective neuronal vulnerability in Alzheimer's disease: Contrasting the vulnerable locus coeruleus to the resilient substantia nigra.

Alexander J Ehrenberg, Cathrine Sant, Felipe L Pereira, Song Hua Li, Jessica Buxton, Sonali Langlois, Marena Trinidad, Ian Oh, Renata Elaine Paraizo Leite, Roberta Diehl Rodriguez and 8 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing 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

8 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Neurotransmitter Systems in Alzheimer's Disease.Current issues in molecular biology · 2026
    Review
  5. Article
  6. Article
  7. Catecholaminergic nucleus integrity and Alzheimer's pathology, symptoms, and progression.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  8. 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

18 authors.

Alexander J EhrenbergMemory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.ORCID 0000-0003-4334-9424
Cathrine SantGladstone Institute for Neurological Diseases, Gladstone Institutes, San Francisco, California, USA.
Felipe L PereiraMemory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
Song Hua LiMemory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
Jessica BuxtonDept. of Integrative Biology, University of California, Berkeley, California, USA.
Sonali LangloisHelen Wills Neuroscience Institute, Dept. of Neuroscience, University of California, Berkeley, California, USA.
Marena TrinidadInnovative Genomics Institute, University of California, Berkeley, California, USA.
Ian OhMemory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
Renata Elaine Paraizo LeiteDept. of Pathology, University of São Paulo Medical School, São Paulo, Brazil.
Roberta Diehl RodriguezDept. of Pathology, University of São Paulo Medical School, São Paulo, Brazil.
Vitor Ribeiro PaesDept. of Pathology, University of São Paulo Medical School, São Paulo, Brazil.
Carlos Agusto PasqualucciDept. of Pathology, University of São Paulo Medical School, São Paulo, Brazil.
William W SeeleyMemory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
Salvatore SpinaMemory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.
Claudia K SuemotoDivision of Geriatrics, University of São Paulo Medical School, São Paulo, Brazil.
Sally TempleNeural Stem Cell Institute, Rensselaer, New York, USA.
Daniela KauferHelen Wills Neuroscience Institute, Dept. of Neuroscience, University of California, Berkeley, California, USA.
Lea T GrinbergMemory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, California, USA.ORCID 0000-0002-6809-0618

Funding

TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
Research Education ComponentP30AG062422 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Katherine P Rankin · 2019 to 2026
$36.9M
PrPSc SPECIFIC INTERACTION WITH NOVEL PrP-Fc FUSION PROTEINSP50AG023501 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MILLER, BRUCE L · 2004 to 2018
$27.1M
Investigating regional and cellular vulnerabilities to tau pathology in young-onset Alzheimer's diseaseR01AG075802 · NIA · MAYO CLINIC JACKSONVILLE · PI BERNARDINO Francesco GHETTI, Lea Tenenholz Grinberg · 2022 to 2026
$15.5M
Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSPR01AG060477 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Lea Tenenholz Grinberg, Thomas C Neylan · 2019 to 2026
$8.2M
Linking Sleep Dysfunction to Tau-related Degeneration across AD ProgressionR01AG064314 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GRINBERG, LEA TENENHOLZ, NEYLAN, THOMAS C · 2019 to 2023
$4.0M
Biology and Biotechnology of Cell and Gene TherapyT32GM139780 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI Amy Elizabeth Herr, Dirk Hockemeyer · 2021 to 2026
$2.4M
Neuropathological changes underlying clinical heterogeneity in Alzheimer diseaseK24AG053435 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GRINBERG, LEA TENENHOLZ · 2016 to 2025
$1.8M
Alzheimer's Association AARG-20-678884Fundacao de Apoio a Pesquisa do Estado de São Paulo 06/55318Fundacao de Apoio a Pesquisa do Estado de São Paulo 2009/09134-4Fundacao de Apoio a Pesquisa do Estado de São Paulo 2012/07526-5NIA NIH HHS K24 AG053435NIA NIH HHS P01 AG019724NIA NIH HHS P30 AG062422NIA NIH HHS P50 AG023501NIA NIH HHS R01 AG060477NIA NIH HHS R01 AG064314NIA NIH HHS R01 AG075802NIGMS NIH HHS T32 GM139780NIH HHS K24AG053435NIH HHS P30 AG062422NIH HHS R01AG060477NIH HHS R01AG064314NIH HHS R01AG075802NIH HHS T32 GM139780Rainwater Charitable FoundationUC Berkeley Greater Good Science CenterUC Berkeley Neuro-AI Resilience Center
6 · The paper itself

Abstract

introductionAlzheimer's disease (AD) selectively affects certain brain regions, yet the mechanisms of selective vulnerability remain poorly understood. The neuromodulatory subcortical system, which includes nuclei exhibiting a range of vulnerability and resilience to AD-type degeneration, presents a framework for uncovering these mechanisms.

methodsWe leveraged transcriptomics and immunohistochemistry in paired samples from human post mortem tissue representing a vulnerable and resilient region-the locus coeruleus (LC) and substantia nigra (SN). These regions have comparable anatomical features but distinct vulnerability to AD.

resultsWe identified significant differences in cholesterol homeostasis, antioxidant pathways, KRAS signaling, and estrogen signaling at a bulk transcriptomic level. Notably, evidence of sigma-2 receptor upregulation was detected in the LC. DISCUSSION: Our findings highlight pathways differentiating the LC and SN, potentially explaining the LC's selective vulnerability in AD. Such pathways offer potential targets of disease-modifying therapies for AD. HIGHLIGHTS: Intraindividual comparative RNAseq was used to study selective vulnerability. Metallothionein genes are significantly enriched in the substantia nigra. Cholesterol homeostatic genes are significantly enriched in the locus coeruleus. The locus coeruleus is likely more susceptible to toxic amyloid beta oligomers.

Indexed as

Alzheimer DiseaseLocus CoeruleusNeuronsSubstantia NigraAgedAged, 80 and overCholesterolFemaleHumansMaleTranscriptomeCholesterolAlzheimer's diseaseautopsycatecholaminesdopaminehumanlocus coeruleusneuropathologynoradrenalinesubstantia nigratauopathytranscriptomics

Identifiers

PMID40135662
PMCPMC11938114

What OpenQuestion holds

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LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

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.