Evidence map›Paper›PMID 41145521›Full record

ArticleNature communications2025

Sex-specific associations of gene expression with Alzheimer's disease neuropathology and ante-mortem cognitive performance.

Mabel Seto, Michelle Clifton, Melisa Lara Gomez, Gillian Coughlan, Katherine A Gifford, Angela L Jefferson, Philip L De Jager, David A Bennett, Yanling Wang, Lisa L Barnes and 4 more

Abstract read
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing 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

10 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Review
  6. Article
  7. Article
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  10. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors.

Mabel Seto *Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8567-2532
Michelle Clifton *Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Melisa Lara GomezVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Gillian CoughlanDepartment of Neurology, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0003-1806-702X
Katherine A GiffordVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Angela L JeffersonVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Philip L De JagerCenter for Translational & Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-8057-2505
David A BennettRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Yanling WangRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-8589-4239
Lisa L BarnesRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Julie A SchneiderRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-9482-1752
Timothy J HohmanVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.ORCID http://orcid.org/0000-0002-3377-7014
Rachel F BuckleyDepartment of Neurology, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-5356-5537
Logan DumitrescuVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA. Logan.C.Dumitrescu@vumc.org.ORCID http://orcid.org/0000-0002-9782-9944

Funding

Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
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
The Vanderbilt Institute for Clinical and Translational Research (VICTR)UL1TR000445 · NCATS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BERNARD, GORDON RAPHAEL · 2012 to 2016
$41.4M
Vanderbilt Memory & Aging ProjectR01AG034962 · NIA · VANDERBILT UNIVERSITY MEDICAL CENTER · PI JEFFERSON, ANGELA L. · 2011 to 2025
$24.1M
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
Discovery of Novel Proteomic Targets in Alzheimer's DiseaseU01AG046161 · NIA · EMORY UNIVERSITY · PI BENNETT, DAVID ALAN, GESCHWIND, DANIEL H · 2014 to 2018
$8.4M
Genetic Epidemiology of Cognitive Decline in an Aging Population SampleR01AG030146 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI EVANS, DENIS A · 2007 to 2018
$6.2M
Neuroprotective Effects of Vascular Endothelial Growth Factor in Alzheimer's DiseaseR01AG061518 · NIA · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Timothy J Hohman · 2019 to 2026
$5.9M
Sex-Specific Genetic Drivers of Alzheimer's Disease EndophenotypesR01AG073439 · NIA · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Logan C Dumitrescu · 2021 to 2026
$4.8M
NCATS NIH HHS UL1 TR000445NIA NIH HHS DP2 AG082342NIA NIH HHS K01 AG049164NIA NIH HHS K24 AG046373NIA NIH HHS P30 AG010161NIA NIH HHS R00 AG061238NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG030146NIA NIH HHS R01 AG034962NIA NIH HHS R01 AG036042NIA NIH HHS R01 AG036836NIA NIH HHS R01 AG048015NIA NIH HHS R01 AG056534NIA NIH HHS R01 AG059716NIA NIH HHS R01 AG061518NIA NIH HHS R01 AG073439NIA NIH HHS R01 AG079142NIA NIH HHS RC2 AG036547NIA NIH HHS RF1 AG057473NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG046161NIA NIH HHS U01 AG061356NIH HHS S10 OD023680NINDS NIH HHS R01 NS100980U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) R01AG073439
6 · The paper itself

Abstract

The biological mechanisms underlying the increased prevalence of Alzheimer's disease (AD) in women remain undefined. While previous case/control studies have identified sex-biased molecular pathways, the sex-specific relationships between gene expression and AD endophenotypes, particularly involving sex chromosomes, are underexplored. With bulk transcriptomic data across 3 brain regions from 767 decedents, we investigated sex-specific associations between gene expression and post-mortem β-amyloid and tau, as well as antemortem longitudinal cognition. Among 23,118 significant gene associations, 10% were sex-specific, with 73% of these identified in females and primarily associated with tau tangles and longitudinal cognition (90%). Notably, four X-linked genes, MCF2, HDAC8, FTX, and SLC10A3, demonstrated significant sex differences in their associations with AD endophenotypes (i.e., significant sex x gene interaction). Our results also uncovered sex-specific biological pathways, including a female-specific role of neuroinflammation and neuronal development, underscoring the importance of sex-aware analyses to advance precision medicine approaches in AD.

Indexed as

Alzheimer DiseaseCognitionAgedAged, 80 and overAmyloid beta-PeptidesAutopsyBrainFemaleGenes, X-LinkedHumansMaleMiddle AgedSex CharacteristicsSex FactorsSymporterstau ProteinsAmyloid beta-PeptidesSymporterstau Proteins

Identifiers

PMID41145521
PMCPMC12559284

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Registered trials

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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.