Revealing the combined roles of Abeta and tau in Alzheimer's disease via a pathophysiological activity decoder

Sanchez-Rodriguez, L. M.; Bezgin, G.; Carbonell, F.; Therriault, J.; Fernandez-Arias, J.; Karikari, T. K. M.; Ashton, N. J.; Benedet, A.; Zetterberg, H.; Blennow, K.; Triana-Baltzer, G.; Kolb, H. C.; Rosa-Neto, P.; Iturria-Medina, Y.

doi:10.1101/2023.02.21.529377

bioRxiv · 10.1101/2023.02.21.529377

Revealing the combined roles of Abeta and tau in Alzheimer's disease via a pathophysiological activity decoder

Sanchez-Rodriguez, L. M.·Bezgin, G.·Carbonell, F.·Therriault, J.·Fernandez-Arias, J.·Karikari, T. K. M.·Ashton, N. J.·Benedet, A.·Zetterberg, H.·Blennow, K.·Triana-Baltzer, G.·Kolb, H. C.·Rosa-Neto, P.·Iturria-Medina, Y.

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Abstract

Neuronal dysfunction and cognitive deterioration in Alzheimers disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we introduce personalized brain activity models incorporating functional MRI, amyloid-{beta} (A{beta}) and tau-PET from AD-related participants (N=132). Within the model assumptions, electrophysiological activity is mediated by toxic protein deposition. Our integrative subject-specific approach uncovers key patho-mechanistic interactions, including synergistic A{beta} and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP). Furthermore, our results reproduce hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with A{beta}-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

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Sanchez-Rodriguez, L. M., Bezgin, G., Carbonell, F., Therriault, J., Fernandez-Arias, J., Karikari, T. K. M., Ashton, N. J., Benedet, A., Zetterberg, H., Blennow, K., Triana-Baltzer, G., Kolb, H. C., Rosa-Neto, P., Iturria-Medina, Y.. 2023-02-22. Revealing the combined roles of Abeta and tau in Alzheimer's disease via a pathophysiological activity decoder. https://doi.org/10.1101/2023.02.21.529377

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