APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction.

Overview

Authors: Qing Yu¹, Fang Du^1,2, Veria Puerta-Alvarado³, Jeffrey H Goodman^2,4, Clarissa L Waites^1,5

ORCID iDs: Veria Puerta-Alvarado, Jeffrey H Goodman, Clarissa L Waites

Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer’s Disease and Aging Brain, Columbia University Irving Medical Center, New York, NY USA
Institute for Basic Research in Developmental Disabilities, Staten Island, NY USA
Neurobiology and Behavior PhD Program, Columbia University, New York, NY USA
Departments of Physiology, Pharmacology, and Neurology, SUNY Downstate Health Sciences University, Brooklyn, NY USA
Department of Neuroscience, Columbia University, New York, NY USA

Institutions: Columbia University Irving Medical Center (United States); Columbia University (United States); SUNY Downstate Health Sciences University (United States)

Journal: Cell death & disease, volume 17, issue 1, article 419

Dates: received 17 February 2025; accepted 2 March 2026; published online 27 March 2026

Type: Research article · Language: English

License: CC BY

Identifiers: DOI 10.1038/s41419-026-08543-1 · PMID 41896522 · PMCID PMC13150023 · OpenAlex W7141458161

Open access: gold, a free copy (OpenAlex)

Status: data only (how the code is found and verified)

Categories: human (organism), mouse (organism), Alzheimer's / dementia (population), Parkinson's (population), cellular / molecular (subfield)

Methods: Statistics, Smoothing, state filtering, decompositions, Evoked potentials

Keywords: Alzheimer's disease, Stress and resilience

MeSH: Apolipoprotein E4*, Glucocorticoids*, Mitochondria*, tau Proteins*, Alzheimer Disease, Animals, Hippocampus, Humans, Mice, Mice, Transgenic, Mitochondrial Membrane Transport Proteins, Mitochondrial Permeability Transition Pore, Neurons, Phosphorylation, Receptors, Glucocorticoid (* major topic)

Topic: Alzheimer's disease research and treatments (Cellular and Molecular Neuroscience, Neuroscience), according to OpenAlex

Funding: U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (R01NS080967); NIA NIH HHS (R01 AG069941, R21 AG085473); U.S. Department of Health & Human Services | NIH | National Institute on Aging (R21AG085473, RF1AG069941); U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) (RF1AG069941, R21AG085473); U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS080967); CUIMC TIGER grant

Citations: cited by 1 paper (Europe PMC); 89 references in the paper

Abstract

APOE4 is the leading genetic risk factor for Alzheimer’s disease, and chronic stress is a leading environmental risk factor. Studies suggest that APOE4 confers vulnerability to the behavioral and neuropathological effects of chronic stress, representing a potential mechanism by which this genetic variant accelerates Alzheimer’s onset and progression. Whether and how APOE4-mediated stress vulnerability manifests in neurons of the hippocampus, a brain region particularly susceptible to stress and Alzheimer’s pathology, remains unexplored. Using a combination of in vivo and in vitro experiments in humanized APOE4 and APOE3 knockin mice and primary hippocampal neurons from these animals, we investigated whether and how APOE4 confers sensitivity to glucocorticoids (GCs), the main stress hormones. We found that a hallmark of stress/GC-induced brain damage, tau pathology (i.e., tau accumulation, hyperphosphorylation, and spreading) is exacerbated in APOE4 versus APOE3 mice. Moreover, APOE4 animals exhibit underlying mitochondrial dysfunction and enhanced glucocorticoid receptor activation in the hippocampus, factors that likely contribute to tau pathogenesis in both the presence and absence of stress/GCs. Supporting this concept, opening of the mitochondrial permeability transition pore (mPTP) drives mitochondrial dysfunction and tau pathology in APOE4 mice, while pharmacological inhibition of the mPTP is protective against ApoE4-mediated mitochondrial damage, tau phosphorylation and spreading, and downstream hippocampal synapse loss. These findings shed light on the mechanisms of stress vulnerability in APOE4 carriers and identify the mPTP as a potential therapeutic target for ameliorating Alzheimer’s pathogenesis in this population.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data and to no code of its authors: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

geo:GSE167497, at NCBI GEO; found in the text, “Clustering, differential expression gene…”

Data availability

The data that support the findings of this study, generated and analyzed in this study, are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 2 keywords, 15 MeSH terms, 6 funders, 89 references.

Cite

This paper

Yu, Q., Du, F., Puerta-Alvarado, V., Goodman, J. H., & Waites, C. L. (2026). APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction. Cell death & disease, 17(1), 419. https://doi.org/10.1038/s41419-026-08543-1

BibTeX

@article{yu2026apoe4, author = {Yu, Qing and Du, Fang and Puerta-Alvarado, Veria and Goodman, Jeffrey H and Waites, Clarissa L}, title = {{APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction}}, journal = {Cell death \& disease}, year = {2026}, month = mar, volume = {17}, number = {1}, pages = {419}, publisher = {Nature Publishing Group}, issn = {2041-4889}, doi = {10.1038/s41419-026-08543-1}, url = {https://doi.org/10.1038/s41419-026-08543-1}, pmid = {41896522}, pmcid = {PMC13150023} }

RIS

TY - JOUR AU - Yu, Qing AU - Du, Fang AU - Puerta-Alvarado, Veria AU - Goodman, Jeffrey H AU - Waites, Clarissa L TI - APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction T2 - Cell death & disease J2 - Cell Death Dis PY - 2026 DA - 2026/03/27 VL - 17 IS - 1 SP - 419 SN - 2041-4889 PB - Nature Publishing Group DO - 10.1038/s41419-026-08543-1 UR - https://doi.org/10.1038/s41419-026-08543-1 LA - en ER -

CSL-JSON

{ "id": "10.1038/s41419-026-08543-1", "type": "article-journal", "title": "APOE4 exacerbates glucocorticoid stress hormone-induced tau pathology via mitochondrial dysfunction", "container-title": "Cell death & disease", "author": [ { "family": "Yu", "given": "Qing" }, { "family": "Du", "given": "Fang" }, { "family": "Puerta-Alvarado", "given": "Veria" }, { "family": "Goodman", "given": "Jeffrey H" }, { "family": "Waites", "given": "Clarissa L" } ], "container-title-short": "Cell Death Dis", "volume": "17", "issue": "1", "page": "419", "DOI": "10.1038/s41419-026-08543-1", "PMID": "41896522", "PMCID": "PMC13150023", "ISSN": "2041-4889", "publisher": "Nature Publishing Group", "URL": "https://doi.org/10.1038/s41419-026-08543-1", "language": "en", "issued": { "date-parts": [ [ 2026, 3, 27 ] ] } }

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion, reproductions, activity

Discussion: code errors and mismatches between the code and the paper about this paper and its code, from readers and its authors, beside the paper and its tracing map.

Reproductions: reports from readers who ran the authors' code and did not get the paper's result, what they ran, with which environment, commit and data.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.