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Cited by 43Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

APOEε4 potentiates amyloid β effects on longitudinal tau pathology

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Ferrari-Souza, João Pedro, Bellaver, Bruna, Ferreira, Pâmela C. L., Benedet, Andréa L., Povala, Guilherme, Lussier, Firoza Z., Leffa, Douglas T., Therriault, Joseph +31 more·2023·Nature Aging
DOI 10.1038/s43587-023-00490-2PMC PMC10592050

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Abstract

Abstract The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOEε4 carriership and amyloid-β (Aβ) burden with longitudinal tau pathology progression. We studied 104 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ ([18F]AZD4694) and tau ([18F]MK-6240) at baseline, as well as a follow-up tau-PET scan (mean follow-up, 2.4 years). We further assessed longitudinal changes in tau phosphorylation (plasma phosphorylated tau at threonine 217 [p-tau217+]), brain atrophy (gray matter density), and clinical function (clinical dementia rating scale sum of boxes). We found that APOEε4 carriership potentiates Aβ effects on longitudinal tau tangle accumulation over two years. The APOEε4-potentiated Aβ effects on tangles were mediated by longitudinal plasma p-tau217+ increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results support a model in which the APOEε4 allele plays a key role in Aβ downstream effects on the aggregation of phosphorylated tau in the form of neurofibrillary tangles in the living human brain.

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Authors
Ferrari-Souza, J. P., Bellaver, B., Ferreira, P. C. L., Benedet, A. L., Povala, G., Lussier, F. Z., Leffa, D. T., Therriault, J., Tissot, C., Soares, C., Wang, Y.-T., Chamoun, M., Servaes, S., Macedo, A. C., Vermeiren, M., Bezgin, G., Kang, M. S., Stevenson, J., Rahmouni, N., Pallen, V., Poltronetti, N. M., Cohen, A., Lopez, O. L., Klunk, W. E., Soucy, J.-P., Gauthier, S., Souza, D. O., Triana-Baltzer, G., Saad, Z. S., Kolb, H. C., Karikari, T. K., Villemagne, V. L., Tudorascu, D. L., Ashton, N. J., Zetterberg, H., Blennow, K., Zimmer, E. R., Rosa-Neto, P., & Pascoal, T. A.
Affiliations
  • Universidade Federal do Rio Grande do Sul (BR)
  • University of Pittsburgh (US)
  • Centre intégré universitaire de santé et de services sociaux de l'Ouest-de-l’Île-de-Montréal (CA)
  • Montreal Neurological Institute and Hospital (CA)
  • University of Toronto (CA)
  • King's College London (GB)
  • University of Wisconsin–Madison (US)
  • Sahlgrenska University Hospital (SE)
Corresponding author
Pascoal, Tharick A.
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2023-09-25
Volume
3
Issue
10
Pages
1210-1218
ISSN
2662-8465 (ISSN-L)
DOI
10.1038/s43587-023-00490-2
PMC
PMC10592050
OpenAlex
W4387013888
Cited by
43
References
61
Citations by year
2026: 14 · 2025: 22 · 2024: 6 · 2023: 1
FWCI
7.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Aging (publishedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Alzheimer's Association (SG-23-1038904 QC, ADSF-21-831377-C, ZEN-21-848495, ADSF‐21‐831376‐C, -21-850325, #ADSF-21-831381-C, SG-23-1038904, 2021 Zenith Award, NIRP-12-259245, AARF-D-22-923814, AARGD-21-850670, AARFD-22-974627, #NIRG‐12‐92090, 850325, ALZ-NAN-22-928381, 34874, 33397, AACSF-20-648075, -21- 831377-C, AARF-21-850325, Serra-1912-31365)
  • Alzheimer's Drug Discovery Foundation (2016862, FO2017-0243, 201809, ADSF-21-831381-C, 2017-00915, UKDRI-1003, #ALFGBG-715986, ZEN-21-848495, 201809–2016862, ADSF-21-831377-C, 860197, JPND2019-466-236, JPND2021-00694, 201809-2016615, #ADSF-21-831376-C, #RDAPB‐201809‐2016615)
  • BrightFocus Foundation (AF-930627, A2020812F)
  • Familjen Erling-Perssons Stiftelse (860197)
  • McGill University (162303, MOP-11-51-31, RFN 152985, 159815)
  • Fondation Brain Canada (CFI Project 34874; 33397, CFI Project 34874, 2020-VICO-279314, 34874, 33397)
  • Stiftelsen för Gamla Tjänarinnor (FO2022‐0270, 860197)
  • Weston Brain Institute
  • EU Joint Programme – Neurodegenerative Disease Research (JPND 2021-00694, JPND2019-466-236)
  • Consortium canadien en neurodégénérescence associée au vieillissement (MOP-11-51-31 -team 1)
  • Cerveau Technologies
  • European Commission (101,053,962, JPND2021‐00694, HORIZON2020, ALFGBG-71320, JPND2019‐466‐236, 860197, 2022-2025)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88887, 88887.336490/2019‐00)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (312306/2021-0, 21/2551-0000673-0)
  • Hjärnfonden (ALZ2022-0006), #FO2022-0270, FO2017‑0243, FO2017, ALFGBG-715986, #FO2020-0240, #ALFGBG-965240, JPND2019-466-236)
  • Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (21/2551- 0000673-0)
  • Vetenskapsrådet (ALFGBG-965240, ALZ2022-0006, #101053962, 2021-03244, 2017-00915, (#ALFGBG-715986, 2022-01018, ALFGBG‐71320, 2022-00732, 2018-, JPND2019-466-236, FO2017-0243, 2018-02532)
  • Alzheimerfonden (#AF-930627, #AF‐968270, AF-930351, AF‐939721)
  • Instituto Serrapilheira (Serra‐1912‐31365)
  • UK Dementia Research Institute (#2017-00915, UKDRI‐ 1003)
  • National Institutes of Health (ZEN-21- 848495)
  • HORIZON EUROPE Framework Programme (101053962, 860197)
  • Canadian Institutes of Health Research (#MOP-11-51-31, 201809, 152985, 159815, RFN 152,985, 162303, MOP-11-51-31; RFN 152985, 2022-2025, 92090)
  • Fonds de Recherche du Québec - Santé (2020-VICO-279314)
  • National Institute on Aging (R01AG068398, R01AG073267, R01AG075336)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid-beta, tau pathology, Alzheimer's disease, tau phosphorylation, p-tau217, tau PET, brain atrophy, clinical deterioration, genetic risk
MeSH terms
Alleles, Alzheimer Disease, Heterozygote, Humans, Magnetic Resonance Imaging, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Apolipoprotein E4

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