Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum

Abstract

Functionally related brain regions are selectively vulnerable to Alzheimer’s disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer’s disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivo molecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer’s disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer’s disease dementia, we found several distinct spatial patterns of tau deposition, including ‘Braak-like’ and ‘non-Braak-like’, across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with ‘non-Braak-like’ patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer’s disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer’s disease.

Regional multimodal relationships between tau, hypometabolism, atrophy, and fractional anisotropy in atypical Alzheimer's disease

“…Studies have suggested that the regional pattern of Aβ deposition is consistent across clinical phenotypes of AD and is not related to neurodegeneration (Bischof et al, 2016; Iaccarino et al, 2018; La Joie et al, 2012; Ossenkoppele et al, 2015; Ossenkoppele et al, 2016; Rabinovici et al, 2008), while tau topographically matches grey matter atrophy and glucose hypometabolism and can therefore be interpreted as the likely driving force behind neurodegeneration (Dronse et al, 2017; Ossenkoppele et al, 2016; Jennifer L Whitwell et al, 2018; Xia et al, 2017). Additionally, it has been observed that AD pathological proteins may spread along functional brain networks, with strongly connected regions displaying a higher tau burden (Cope et al, 2018; Hoenig et al, 2018; Jones et al, 2017) and amyloid being a partial mediator between functional network failure and tau deposition (Jones et al, 2017). The majority of these studies have assessed the spectrum of AD clinical presentations, including both typical and atypical variants.…”

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

“…Aβ disrupts synaptic functioning, resulting in aberrant brain connectivity at the synaptic level (Selkoe, 2002; Spires‐Jones & Hyman, 2014), as well as on the whole‐brain connectivity level (Delbeuck, der Linden, & Collette, 2003; Hedden et al., 2009). Although the precise sequence of events caused by Aβ plaques is still being investigated (Altmann, Ng, Landau, Jagust, & Greicius, 2015) and interactions with other agents recognized (Jones et al., 2017), the key role of Aβ in AD pathology is beyond doubt (Jack et al., 2016). …”

Data-driven approaches for Tau-PET imaging biomarkers in Alzheimer’s disease

“…The improvement observed is likely due to the data-driven nature of the method used for derivation of the clusters. 47 .…”