<i>APOE</i>ε4 associates with microglial activation independently of Aβ plaques and tau tangles

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Abstract

Animal studies suggest that the apolipoprotein E ε4 ( APOEε4) allele is a culprit of early microglial activation in Alzheimer’s disease (AD). Here, we tested the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [ ¹⁸F]AZD4694), tau ([ ¹⁸F]MK6240), and microglial activation ([ ¹¹C]PBR28). We found that APOEε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.

Abstract

APOEε4 contributes to microglial activation in early Braak regions, promoting Alzheimer’s disease progression.

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Most cited references 79

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lavaan: AnRPackage for Structural Equation Modeling

Yves Rosseel (2012)

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The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

Guy M McKhann, David S. Knopman, Howard Chertkow … (2011)

The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia. Copyright © 2011. Published by Elsevier Inc.

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Neuropathological stageing of Alzheimer-related changes

H Braak, E Braak (1991)

Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.

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Author and article information

Contributors

João Pedro Ferrari-Souza:

ORCID: https://orcid.org/0000-0003-2183-1551

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Firoza Z. Lussier:

ORCID: https://orcid.org/0000-0002-6877-4825

Role: Data curationRole: Formal analysisRole: InvestigationRole: Writing - review & editing

Douglas T. Leffa:

ORCID: https://orcid.org/0000-0002-4890-8451

Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Writing - review & editing

Joseph Therriault:

ORCID: https://orcid.org/0000-0002-7826-4781

Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Cécile Tissot:

ORCID: https://orcid.org/0000-0003-2711-3833

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: Writing - review & editing

Bruna Bellaver:

ORCID: https://orcid.org/0000-0002-2212-3373

Role: ConceptualizationRole: MethodologyRole: SoftwareRole: Writing - review & editing

Pâmela C. L. Ferreira:

ORCID: https://orcid.org/0000-0003-2134-9829

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: ValidationRole: VisualizationRole: Writing - review & editing

Maura Malpetti:

ORCID: https://orcid.org/0000-0001-8923-9656

Role: ConceptualizationRole: ValidationRole: Writing - review & editing

Yi-Ting Wang: Role: InvestigationRole: ValidationRole: Writing - review & editing

Guilherme Povala:

ORCID: https://orcid.org/0000-0002-2023-6569

Role: ConceptualizationRole: InvestigationRole: SoftwareRole: VisualizationRole: Writing - original draft

Andréa L. Benedet:

ORCID: https://orcid.org/0000-0001-8219-1741

Role: Data curationRole: Project administrationRole: ResourcesRole: Writing - review & editing

Nicholas J. Ashton: Role: ConceptualizationRole: InvestigationRole: Resources

Mira Chamoun:

ORCID: https://orcid.org/0000-0001-7001-5652

Role: InvestigationRole: Project administrationRole: ResourcesRole: Supervision

Stijn Servaes:

ORCID: https://orcid.org/0000-0002-4431-957X

Role: Data curationRole: SoftwareRole: Writing - review & editing

Gleb Bezgin: Role: Data curationRole: Formal analysisRole: SoftwareRole: SupervisionRole: ValidationRole: Writing - review & editing

Min Su Kang:

ORCID: https://orcid.org/0000-0003-0745-6222

Role: Data curationRole: Formal analysisRole: InvestigationRole: ResourcesRole: Validation

Jenna Stevenson: Role: Project administration

Nesrine Rahmouni: Role: InvestigationRole: Project administrationRole: Supervision

Vanessa Pallen: Role: Investigation

Nina Margherita Poltronetti: Role: Data curationRole: InvestigationRole: Writing - review & editing

John T. O’Brien:

ORCID: https://orcid.org/0000-0002-0837-5080

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing

James B. Rowe:

ORCID: https://orcid.org/0000-0001-7216-8679

Role: MethodologyRole: Writing - review & editing

Ann D. Cohen: Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draft

Oscar L. Lopez:

ORCID: https://orcid.org/0000-0002-8546-8256

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - review & editing

Dana L. Tudorascu: Role: Formal analysis

Thomas K. Karikari:

ORCID: https://orcid.org/0000-0003-1422-4358

Role: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Writing - review & editing

William E. Klunk: Role: ConceptualizationRole: SupervisionRole: Writing - review & editing

Victor L. Villemagne: Role: SupervisionRole: Writing - review & editing

Jean-Paul Soucy: Role: InvestigationRole: Writing - review & editing

Serge Gauthier: Role: MethodologyRole: Visualization

Diogo O. Souza: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: ResourcesRole: VisualizationRole: Writing - review & editing

Henrik Zetterberg:

ORCID: https://orcid.org/0000-0003-3930-4354

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing

Kaj Blennow:

ORCID: https://orcid.org/0000-0002-1890-4193

Role: InvestigationRole: Writing - review & editing

Eduardo R. Zimmer:

ORCID: https://orcid.org/0000-0002-5349-0053

Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: VisualizationRole: Writing - review & editing

Pedro Rosa-Neto:

ORCID: https://orcid.org/0000-0001-9116-1376

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing - review & editing

Tharick A. Pascoal:

ORCID: https://orcid.org/0000-0001-9057-8014

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: April 2023

Publication date (Electronic, pub): 05 April 2023

Volume: 9

Issue: 14

Electronic Location Identifier: eade1474

Affiliations

[ ¹ ]Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

[ ² ]Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

[ ³ ]Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.

[ ⁴ ]ADHD Outpatient Program and Development Psychiatry Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.

[ ⁵ ]Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, UK.

[ ⁶ ]Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

[ ⁷ ]Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.

[ ⁸ ]Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK.

[ ⁹ ]Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

[ ¹⁰ ]Artificial Intelligence and Computational Neurosciences lab, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.

[ ¹¹ ]LC Campbell Cognitive Neurology Unit, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada.

[ ¹² ]Department of Psychiatry, University of Cambridge, Cambridge, UK.

[ ¹³ ]MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.

[ ¹⁴ ]Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.

[ ¹⁵ ]Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.

[ ¹⁶ ]Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.

[ ¹⁷ ]UK Dementia Research Institute at UCL, London, UK.

[ ¹⁸ ]Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.

[ ¹⁹ ]Department of Pharmacology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

[ ²⁰ ]Graduate Program in Biological Sciences: Pharmacology and Therapeuctis, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Author notes

[* ]Corresponding author. Email: pascoalt@ 123456upmc.edu .

[†]

These authors contributed equally to this work.

Author information

João Pedro Ferrari-Souza https://orcid.org/0000-0003-2183-1551

Firoza Z. Lussier https://orcid.org/0000-0002-6877-4825

Douglas T. Leffa https://orcid.org/0000-0002-4890-8451

Joseph Therriault https://orcid.org/0000-0002-7826-4781

Cécile Tissot https://orcid.org/0000-0003-2711-3833

Bruna Bellaver https://orcid.org/0000-0002-2212-3373

Pâmela C. L. Ferreira https://orcid.org/0000-0003-2134-9829

Maura Malpetti https://orcid.org/0000-0001-8923-9656

Guilherme Povala https://orcid.org/0000-0002-2023-6569

Andréa L. Benedet https://orcid.org/0000-0001-8219-1741

Mira Chamoun https://orcid.org/0000-0001-7001-5652

Stijn Servaes https://orcid.org/0000-0002-4431-957X

Min Su Kang https://orcid.org/0000-0003-0745-6222

John T. O’Brien https://orcid.org/0000-0002-0837-5080

James B. Rowe https://orcid.org/0000-0001-7216-8679

Oscar L. Lopez https://orcid.org/0000-0002-8546-8256

Thomas K. Karikari https://orcid.org/0000-0003-1422-4358

Henrik Zetterberg https://orcid.org/0000-0003-3930-4354

Kaj Blennow https://orcid.org/0000-0002-1890-4193

Eduardo R. Zimmer https://orcid.org/0000-0002-5349-0053

Pedro Rosa-Neto https://orcid.org/0000-0001-9116-1376

Tharick A. Pascoal https://orcid.org/0000-0001-9057-8014

Article

Publisher ID: ade1474

DOI: 10.1126/sciadv.ade1474

PMC ID: 10075966

PubMed ID: 37018391

SO-VID: 40f84fdc-791c-4472-95b3-d18ae12fa84e

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 27 July 2022

Date accepted : 02 March 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: #R01AG075336 and #R01AG073267

Funded by: FundRef http://dx.doi.org/10.13039/100000874, Brain and Behavior Research Foundation;

Award ID: #29486

Funded by: FundRef http://dx.doi.org/10.13039/100012479, Weston Brain Institute;

Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Award ID: #MOP-11-51-31; RFN 152985, 159815, 162303

Funded by: FundRef http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;

Award ID: #200691/2021-0

Funded by: FundRef http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;

Award ID: #166407/2020-8

Funded by: Canadian consortium of Neurodegeneration and aging;

Award ID: #MOP-11-51-31 - team 1

Funded by: Fonds de recherche du Québec – Santé;

Funded by: Race Against Dementia Alzheimer’s Research UK;

Award ID: #ARUK-RADF2021A-010

Funded by: Fonds de recherche du Québec – Santé;

Award ID: #2020-VICO-279314

Funded by: Brain Canada Foundation;

Award ID: CFI Project 34874; 33397

Funded by: Alzheimer’s Association;

Award ID: #NIRG-12-92090 and #NIRP-12-259245

Funded by: Alzheimer’s Association;

Award ID: #AACSF-20-648075

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APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles

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Functional role of amyloid

Most cited references 79

lavaan: AnRPackage for Structural Equation Modeling

The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

Neuropathological stageing of Alzheimer-related changes

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