APOEε4 potentiates the effects of Aβ pathology on the deposition of neurofibrillary tangles via tau phosphorylation
João Pedro Ferrari‐Souza, Bruna Bellaver, Pamela C.L. Ferreira, Andrea Lessa Benedet, Guilherme Povala, Firoza Z Lussier, Douglas Teixeira Leffa, Joseph Therriault, Cécile Tissot, Carolina Soares, Yi‐Ting Wang, Mira Chamoun, Stijn Servaes, Arthur C. Macedo, Marie Vermeiren, Gleb Bezgin, Min Su Kang, Jenna Stevenson, Nesrine Rahmouni, Vanessa Pallen, Nina Margherita Poltronetti, Annie Cohen, Oscar L. Lopez, William E Klunk, Jean‐Paul Soucy, Serge Gauthier, Diogo O. Souza, Gallen Triana‐Baltzer, Ziad S. Saad, Hartmuth C. Kolb, Thomas K Karikari, Victor L Villemagne, Dana Tudorascu, Nicholas J. Ashton, Henrik Zetterberg, Kaj Blennow, Eduardo R Zimmer, Pedro Rosa‐Neto, Tharick A. Pascoal- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
The mechanisms by which the apolipoprotein E e4 (APOEe4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOEe4 carriership and amyloid‐ß (Aß) burden with longitudinal tau pathology progression.
Method
We studied 104 individuals across the aging and AD clinical spectrum from the McGill TRIAD cohort. Study participants underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aß ([18F]AZD4694) and tau ([18F]MK6240) at baseline, as well as an additional 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).
Result
We found that APOEe4 carriership potentiates Aß effects on longitudinal tau tangle accumulation over two years (Figure 1). Interestingly, the APOEe4‐potentiated Aß effects on tangles were mediated by longitudinal plasma p‐tau217+ increase (Figure 2). In addition, this longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline during the follow‐up period (Figure 3).
Conclusion
Our results support a model in which the APOEe4 allele plays a key role in Aß downstream effects on the aggregation of phosphorylated tau in the form of neurofibrillary tangles in the living human brain, which is a key factor in the development of dementia. These observations have important implications for the design of future trials by suggesting that the combination of therapies targeting both ApoeE4 and Aß pathology might have the potential to synergistically halt tau progression in AD.