Evidence map›Paper›PMID 42548036›Full record

ArticleAnnals of neurology2026

Genetic Modifiers of ABCA1 Activity Interact with APOE Isoforms to Mediate Alzheimer's Disease Risk.

Andrés Peña-Tauber, Ricardo Hernández Arriaza, Dylan Reil, Manon Muntaner, Junyoung Park, Benjamin Grenier-Boley, Marc Hulsman, Philippe Amouyel, Céline Bellenguez, Camille Charbonnier and 15 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of neurology, 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.

Andrés Peña-TauberDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.ORCID https://orcid.org/0000-0001-9501-4920
Ricardo Hernández ArriazaDepartment of Chemistry, Stanford University, Stanford, CA, USA.
Dylan ReilDepartment of Biochemistry, Stanford University, Stanford, CA, USA.
Manon MuntanerUniv. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Junyoung ParkDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Benjamin Grenier-BoleyUniv. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Marc HulsmanGenomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Philippe AmouyelUniv. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Céline BellenguezUniv. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Camille CharbonnierUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Biostatistics and CNRMAJ, Rouen, France.
Jean-François DeleuzeCommissariat à L'energie Atomique et Aux Energies Alternatives, Centre National de Recherche en Génomique Humaine, Université Paris-Saclay, Gif-sur-Yvette, France.
Orio Dols-IcardoDepartment of Neurology, II B Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
John HardyReta Lila Weston Research Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology, London, UK.
Henne HolstegeGenomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Gaël NicolasUniv Rouen Normandie, Inserm U1245 and CHU Rouen, Department of Genetics and CNRMAJ, Rouen, France.
Simon MeadMedical Research Council Prion Unit at University College London, University College London Institute of Prion Diseases, London, UK.
Michael WagnerDepartment of Old Age Psychiatry and Cognitive Disorders, University Hospital Bonn, Bonn, Germany.
Alfredo RamirezDepartment of Old Age Psychiatry and Cognitive Disorders, University Hospital Bonn, Bonn, Germany.
Rebecca SimsMedical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK.
John van SwietenDepartment of Neurology, Erasmus Medical Centre, Rotterdam, the Netherlands.
Julie WillamsUK Dementia Research Institute & Moondance Dementia Research Laboratory, Dept Psychological Medicine, Cardiff University.
Jean-Charles LambertUniv. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Chaitan KhoslaDepartment of Chemistry, Stanford University, Stanford, CA, USA.
Yann Le GuenDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.ORCID https://orcid.org/0000-0001-6649-8364
Michael D GreiciusDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.

Funding

THE NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE SITEU24AG041689 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LI-SAN WANG · 2012 to 2026
$42.3M
Supplement to Enhance Wellness and Resiliency in the Graduate EnvironmentT32GM007276 · NIGMS · STANFORD UNIVERSITY · PI MORRISON, ASHBY J. · 1985 to 2023
$32.9M
Stanford Alzheimer's Disease Research CenterAdmin Supp: Developing iPSC models for AD and PDP30AG066515 · NIA · STANFORD UNIVERSITY · PI Lisa Goldman Rosas · 2020 to 2026
$29.0M
Illuminating the APOE Locus with Long-Read Sequencing and Targeted GenomicsR35AG072290 · NIA · STANFORD UNIVERSITY · PI GREICIUS, MICHAEL D · 2021 to 2025
$4.6M
NIA NIH HHS P30 AG066515NIA NIH HHS R35 AG072290NIA NIH HHS U24 AG041689NIGMS NIH HHS T32 GM007276Wellcome Trust
6 · The paper itself

Abstract

objectiveATP-binding cassette transporter A1 (ABCA1) has been associated with Alzheimer's disease (AD), but the mechanisms by which it impacts disease risk are unknown. ABCA1 is known to bind apolipoprotein E (ApoE) and catalyze apolipoprotein lipidation. We explored whether genetic variants altering ABCA1 function interact with APOE isoforms to modify AD risk.

methodsUsing data from the Alzheimer's Disease Sequencing Project (ADSP), UK Biobank, and the Alzheimer Disease European Sequencing consortium, we assessed the impact of ABCA1 variants on AD risk in APOE subgroups and tested for statistical interactions with APOE ε2 and ε4 in an all-APOE cohort. We first examined damaging nonsynonymous ABCA1 variants previously associated with AD. We then constructed a measure of predicted ABCA1 activity based on HDL-associated variants and tested its association with AD risk. Finally, we explored potential pathogenic mechanisms of missense variants of interest.

resultsDamaging nonsynonymous ABCA1 variants had differential AD risk effects between APOE genotype groups and exhibited interaction effects with APOE ε2 and ε4. Predicted ABCA1 activity based on HDL-associated variants was associated with reduced AD risk and interacted with APOE ε4. Replication analyses suggested similar differences in effect size of ABCA1 variants between APOE groups and had concordant effect directions, although not statistically significant, in the APOE interaction model. ABCA1 missense variants N1800H and E1172D were strongly associated with plasma HDL and interacted with APOE in AD risk. In cell-based assays, ABCA1-N1800H showed plasma membrane localization defects potentially driven by misfolding.

interpretationGenetic modifiers of ABCA1 activity interact with APOE isoforms to alter AD risk. ANN NEUROL 2026;100:737-750.

Indexed as

Alzheimer DiseaseApolipoproteins EATP Binding Cassette Transporter 1Genetic Predisposition to DiseaseApolipoprotein E4FemaleHumansMaleProtein IsoformsABCA1 protein, humanApolipoprotein E4Apolipoproteins EATP Binding Cassette Transporter 1Protein Isoforms

Identifiers

PMID42548036
PMCPMC13587109

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.