Evidence map›Paper›PMID 42902099›Full record

ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2026

H3K9me3 inhibition reverses Alzheimer's progression by restoring synaptic and immune proteostasis across the brain-retina axis.

Dieu-Trang Fuchs, Jean-Philippe Vit, Altan Rentsendorj, Yosef Koronyo, Julia Sheyn, Bhakta Prasad Gaire, Saba Shahin, Haoshen Shi, Oksana Chepurna, Miyah R Davis and 11 more

Abstract read
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In one paragraph

Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 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

21 authors.

Dieu-Trang Fuchs *Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Jean-Philippe Vit *Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Altan Rentsendorj *Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Yosef KoronyoDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Julia SheynDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Bhakta Prasad GaireDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Saba ShahinDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Haoshen ShiDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Oksana ChepurnaDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Miyah R DavisDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Jered W WilsonDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Stuart L GrahamMacquarie University, Sydney, New South Wales, Australia.
Vivek K GuptaMacquarie University, Sydney, New South Wales, Australia.
Lon S SchneiderDepartment of Psychiatry and The Behavioral Sciences, Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Michael T KleinmanDepartment of Environmental and Occupational Health, College of Health Sciences, University of California, Irvine, California, USA.
Tao SunDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Margaret FahnestockDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
David A HorneDepartment of Cancer Biology and Molecular Medicine, City of Hope National Medical Center, Duarte, California, USA.
Mehdi MirzaeiMacquarie University, Sydney, New South Wales, Australia.
Keith L BlackDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Maya Koronyo-HamaouiDepartment of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.ORCID https://orcid.org/0000-0003-2864-8442

Funding

USCADRC Diversity Supplement PachicanoP30AG066530 · NIA · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HELENA Chang CHUI, ARTHUR W TOGA · 2020 to 2026
$27.8M
Alzheimer's Disease Hallmark Pathology and Associated Inflammation in the RetinaR01AG055865 · NIA · CEDARS-SINAI MEDICAL CENTER · PI Maya Koronyo-Hamaoui · 2018 to 2026
$4.9M
Retinal Imaging of Alzheimer's Disease PathologyR01AG056478 · NIA · CEDARS-SINAI MEDICAL CENTER · PI KORONYO-HAMAOUI, MAYA · 2017 to 2021
$2.5M
National Institutes of Health (NIH)/National Institute on Aging (NIA) AG056478-04S1National Institutes of Health (NIH)/National Institute on Aging (NIA) P30AG066530National Institutes of Health (NIH)/National Institute on Aging (NIA) R01AG055865National Institutes of Health (NIH)/National Institute on Aging (NIA) R01AG056478The Health Effects and Brain Tumor FoundationThe Snyder foundation
6 · The paper itself

Abstract

introductionEpigenetic dysregulation is increasingly linked to aging and neurodegeneration, yet its contribution to retinal and brain pathology in Alzheimer's disease (AD) remains unclear.

methodsWe quantified the repressive epigenetic mark histone H3 lysine 9 trimethylation (H3K9me3) in post mortem retinas and brains from donors spanning normal cognition, mild cognitive impairment, and AD dementia. Using a multi-enzyme methyltransferase panel, we characterized the in vitro inhibitory activity of ETP69, an epidithiodiketopiperazine, against suppressor of variegation 3-9 homologue 1 (SUV39H1) and other methyltransferases. In two transgenic AD mouse models (APPswe/PS1dE9 and APPswe/tauP301L/PS1

resultsH3K9me3 increased early across the AD continuum in both brain and retina, correlating with cognitive impairment and neuropathological burden. H3K9me3 levels were strongly correlated between matched brains and retinas (r = 0.72, p = 0.0002). ETP69 substantially inhibited SUV39H1 and several other methyltransferases in cell-free assays, while consistently reducing cerebral H3K9me3 in vivo relative to other histone marks assessed. In mice, pharmacological H3K9me3 reduction mitigated AD-like pathology, preserved synapses, and improved short- and long-term cognitive and visual performance. Proteomics revealed that H3K9me3 derepression re-established retinal and brain proteostasis and remodeled innate immune pathways and brain-derived neurotrophic factor/nerve growth factor-inducible protein (BDNF/VGF)-granin signaling. DISCUSSION: This study identifies H3K9me3 accumulation as a shared, reversible epigenetic contributor to AD across the retina-brain axis; its reduction represents a promising disease-modifying strategy, and the retina may provide an accessible readout of brain epigenetic dysfunction.

Indexed as

Alzheimer DiseaseBrainHistonesProteostasisRetinaSynapsesAgedAged, 80 and overAnimalsCognitive DysfunctionDisease Models, AnimalDisease ProgressionEpigenesis, GeneticFemaleHumansMaleHistonesgranin family membersheterochromatinhistone modificationneurodegenerative diseaseNT1721ocular manifestations

Identifiers

PMID42902099
PMCPMC13683561

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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.