APOEε4 potentiates Aβ effects on longitudinal tangle accumulation via tau phosphorylation
Author:
Ferrari-Souza João Pedro1, Bellaver Bruna1, Ferreira Pâmela, Benedet Andrea2, Povala Guilherme1, Lussier Firoza1, Leffa Douglas1, Therriault Joseph3ORCID, Tissot Cécile3ORCID, Soares Carolina1ORCID, Wang Yi-Ting3, Chamoun Mira3, Servaes Stijn3, Macedo Arthur3, Vermeiren Marie3, Bezgin Gleb3, Kang Min Su4ORCID, Stevenson Jenna3, Rahmouni Nesrine3, Pallen Vanessa3, Poltronetti Nina3, Cohen Ann1, Lopez Oscar1, Klunk William1, Soucy Jean-Paul3, Gauthier Serge3, Souza Diogo5, Triana-Baltzer Gallen6, Saad Ziad6, Kolb Hartmuth6ORCID, Karikari Thomas7ORCID, Villemagne Victor1, Tudorascu Dana1, Ashton Nicholas7, Zetterberg Henrik7ORCID, Blennow Kaj7ORCID, Zimmer Eduardo5, Rosa-Neto Pedro3ORCID, Pascoal Tharick1ORCID
Affiliation:
1. University of Pittsburgh 2. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden 3. McGill University 4. Sunnybrook Health Sciences Centre 5. Universidade Federal do Rio Grande do Sul 6. Janssen Research & Development 7. University of Gothenburg
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.
Publisher
Research Square Platform LLC
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