Disentangling the distal association between β-Amyloid and tau pathology at varying stages of tau deposition

Abstract

AbstractStudies on the histopathology of Alzheimer’s disease (AD) strongly suggest that extracellular β-amyloid (Aβ) plaques promote the spread of neurofibrillary tau tangles. Despite well-documented spatial discrepancies between these two proteinopathies, their association remains elusive. In this study, we aimed to investigate the distal (non-local) association between tau and Aβ deposition by studying the Aβ, and tau positron emission tomography (PET) scans of 572 elderly subjects, aged 67.11 ± 6.08 years (476 healthy controls (HC), 14 with mild cognitive impairment (MCI), 82 mild AD). We also leveraged 47 tau-PET and 97 Aβ-PET scans of healthy young individuals (aged 20-40) to find regional cut-points for tau- and Aβ-positivity in 68 cortical regions in the brain. Based on these cut-points, we implemented a pseudo longitudinal technique to categorize the elderly subjects into four pathologic phases of AD progression: a no-tau phase, a pre-acceleration phase, an acceleration phase, and a post-acceleration phase. We then assessed the distal association between tau and Aβ in each phase using multiple linear regression models. First, we show that the association between tau and Aβ starts distally in medial temporal lobe (MTL) regions of tau (e.g., left and right entorhinal cortex and right parahippocampal gyrus) in the early stage of tau aggregation (pre-acceleration phase). We then show that tau in several bilateral brain regions (particularly the entorhinal cortex and parahippocampal gyrus) exhibits strong distal associations with Aβ in several cortical brain regions during the acceleration phase. We found a weak distal association in the post-acceleration phase, comprising 96% of MCI or mild AD and Aβ+ subjects. Most importantly, we show that the HC Aβ+ subjects have the highest degree of distal association between tau and Aβ of all the subjects in the acceleration phase. The results of this study characterize the distal association between the two key proteinopathies of AD. This information has potential use for understanding disease progression in the brain and for the development of anti-tau therapeutic agents.