Local and distant relationships between amyloid, tau and neurodegeneration in Alzheimer's Disease

Abstract

The relationships between β-amyloid (Aβ), tau and neurodegeneration within Alzheimer's Disease pathogenesis are not fully understood. To explore these associations in vivo, we evaluated 30 Aβ PET-positive patients (mean ± sd age 62.4 ± 8.3) with mild probable AD and 12 Aβ PET-negative healthy controls (HC) (mean ± sd age 77.3 ± 6.9) as comparison. All participants underwent 3 T MRI, 11C-PiB (Aβ) PET and 18F-AV1451 (tau) PET. Multimodal correlation analyses were run at both voxel- and region-of-interest levels. 11C-PiB retention in AD showed the most diffuse uptake pattern throughout association neocortex, whereas 18F-AV1451 and gray matter volume reduction (GMR) showed a progressive predilection for posterior cortices (p<0.05 Family-Wise Error-[FWE]-corrected). Voxel-level analysis identified negative correlations between 18F-AV1451 and gray matter peaking in medial and infero-occipital regions (p<0.01 False Discovery Rate-[FDR]-corrected). 18F-AV1451 and 11C-PiB were positively correlated in right parietal and medial/inferior occipital regions (p<0.001 uncorrected). 11C-PiB did not correlate with GMR at the voxel-level. Regionally, 18F-AV1451 was largely associated with local/adjacent GMR whereas frontal 11C-PiB correlated with GMR in posterior regions. These findings suggest that, in mild AD, tau aggregation drives local neurodegeneration, whereas the relationships between Aβ and neurodegeneration are not region specific and may be mediated by the interaction between Aβ and tau.

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

“…within a lobe, as another study observed in a cohort of AD patients (Iaccarino et al, 2018). Specifically, we found strong correlations between tau deposition and both hypometabolism and atrophy in the occipital lobes, as well as between tau deposition and hypometabolism in the frontal lobes across the atypical AD cohort.…”

“…This knowledge is essential to understand the causes of neurodegeneration and inform new treatments tailored to address the pathophysiology of the 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).…”

“…We did not investigate spatial relationships involving Aβ-PET uptake, since the population of patients we analyzed was at an advanced stage of the disease and therefore the already widespread amyloid was unlikely to reveal spatial association with the other imaging modalities. Indeed, other studies already highlighted the absence of regional associations between Aβ deposition and neurodegeneration (Iaccarino et al, 2018;Ossenkoppele et al, 2015Ossenkoppele et al, , 2016 or even a mild opposite trend between the two (Bischof et al, 2016).…”

Tau pathology in cognitively normal older adults

“…Lower hippocampal volume has also been associated with greater tau radiotracer retention in the hippocampus [8,10]. Longitudinal studies including individuals ranging from CN to demented have further found that higher baseline tau tracer retention is associated with greater rates of brain volume loss [11,12] and global cognitive decline [13–15].…”

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

“…While the association between increased oxidative stress and increasing bioenergetic dysfunction, as evidenced by increasing glucose hypometabolism, increased lactate and pyruvate and the development of increasing synaptic dysfunction seen in preclinical AD and APOE ε4 carriers, is not associated with Aβ accumulation [257] (reviewed by [258]), recent research suggests that this might not be the case for tau deposition although findings are mixed [259][260][261]. For example, Bischof and others and Kang et al reported a positive correlation between tau deposition and glucose hypometabolism in cross-sectional studies [259,261].…”