Evidence map›Paper›PMID 42726290›Full record

ArticleActa neuropathologica2026

Molecular programs in human locus coeruleus link APOE and neuromelanin to Alzheimer's vulnerability.

Bernard Mulvey, Heena R Divecha, Madhavi Tippani, Svitlana V Bach, Rahul Bharadwaj, Ishbel Del Rosario, Sarah E Maguire, Ryan A Miller, Aaron J Salisbury, Atharv Chandra and 15 more

Abstract read
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In one paragraph

Article in Acta neuropathologica, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

25 authors.

Bernard Mulvey *Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-0815-0436
Heena R Divecha *Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-1959-0675
Madhavi TippaniLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-6465-6418
Svitlana V BachLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-1134-9585
Rahul BharadwajLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-7749-8682
Ishbel Del RosarioLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-6225-0660
Sarah E MaguireLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0009-0005-2884-4787
Ryan A MillerLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-3477-7443
Aaron J SalisburyLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-6777-5826
Atharv ChandraLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0009-0000-3019-7308
Beau A OsterLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-0758-550X
Kelsey D MontgomeryLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-8420-0138
Sang Ho KwonLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-5328-0956
Haya A AlgrainLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-8346-5617
Alexis R PaparielloLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-6746-5054
Louise A Huuki-MyersLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
Joel E KleinmanLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-4210-6052
Leonardo Collado-TorresLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-2140-308X
Thomas M HydeLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-8746-3037
Shizhong HanLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-5114-6742
Stephanie C HicksDepartment of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-7858-0231
Daniel R WeinbergerLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. drweinberger@libd.org.ORCID http://orcid.org/0000-0003-2409-2969
Stephanie C PageLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-1951-7398
Kristen R MaynardLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-0031-8468
Keri MartinowichLieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. keri.martinowich@libd.org.ORCID http://orcid.org/0000-0002-5237-0789

Funding

INTERDISCIPLINARY TRAINING PROGRAM IN NEUROSCIENCEST32MH015330 · NIMH · JOHNS HOPKINS UNIVERSITY · PI MARGOLIS, RUSSELL L · 1985 to 2024
$6.2M
Impact of neuromelanin and Tau accumulation during aging and disease on local gene expression in the human locus coeruleus using spatially-resolved transcriptomics with protein detectionR01AG085933 · NIA · LIEBER INSTITUTE, INC. · PI Stephanie Carinne Hicks, Keri Martinowich · 2024 to 2026
$2.5M
NIH HHS R01AG085933NIH HHS T32MH015330
6 · The paper itself

Abstract

The locus coeruleus (LC) is a small noradrenergic nucleus in the dorsal pons that sends widespread projections across the brain to regulate sleep, arousal, and cognition. LC neurons show early accumulation of phosphorylated tau (pTau) and are particularly vulnerable to degeneration in Alzheimer's disease (AD). AD is also associated with loss of neuromelanin (NM) pigmentation in LC neurons, and NM-sensitive neuroimaging predicts clinical severity and future disease progression. To better understand molecular vulnerability of the LC, we generated spatially resolved transcriptomics data on LC tissue sections from 33 neurotypical middle-aged human brain donors, stratified by AD risk factors including sex, African or European ancestry, and APOE haplotype (E4 risk or E2 protective allele carriers). Comparing across APOE haplotypes, we identify reduced astrocytic gene expression proximal to LC neurons in E4 carriers, in addition to ancestry-specific differences in LC gene expression. Cell-resolution in situ sequencing further demonstrated that APOE differences in LC regional gene expression were partially driven by astrocytes, with more marked haplotype effects in donors of European ancestry. Quantifying gene expression as a factor of local NM content, we find that higher APOE gene expression correlates with reduced NM, and that NM-associated genes are enriched for aging-related pathways. Using the in situ data to analyze NM content in individual LC neurons validated NM associations with expression of APOE, norepinephrine metabolism genes, and genes involved in autophagy. Together, these data suggest that AD risk factors modulate LC vulnerability via molecular processes intrinsic to both noradrenergic neurons and local astrocytes.

Indexed as

Alzheimer DiseaseApolipoproteins ELocus CoeruleusMelaninsAgedAstrocytesFemaleHaplotypesHumansMaleMiddle AgedNeuronsApoE protein, humanApolipoproteins EMelaninsneuromelanin

Identifiers

PMID42726290

What OpenQuestion holds

Textmetadata
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.