Tau and amyloid β proteins distinctively associate to functional network changes in the aging brain

Abstract

INTRODUCTION Misfolded Tau and amyloid-β (Aβ) proteins progressively accumulate in the brain, causing decreased and increased neuronal function and neurodegeneration. This study sought to investigate whether the wide spectrum of functional reorganization in aging brains of cognitively normal individuals relates to specific pathological patterns of Tau and Aβ deposits. METHODS We used functional connectivity neuroimaging and in vivo Tau and Aβ positron emission tomography (PET) scans to study cortical spatial relationships between imaging modalities. RESULTS We found that a negative association between Tau and functional connectivity combined with a positive association between Aβ and functional connectivity is the most frequent cortical pattern among elderly subjects. Moreover, we found specific brain areas that interrelate hypo- and hyper-connectivity regions. DISCUSSION Our findings have critical implications to understanding how the two main elements of AD-related pathology affect the aging brain and how they cause alterations in large-scale neuronal circuits.

Association of deposition of tau and amyloid‐β proteins with structural connectivity changes in cognitively normal older adults and Alzheimer’s disease spectrum patients

“…In the amyloid‐negative CN group with low tau deposition, we found increased connectivity due to tau deposition in the bilateral hippocampi, temporal lobes, and entire cerebrum. This is consistent with previous studies demonstrating increased functional connectivity in relation to higher tau tracer uptake, and can be explained as a compensatory response (Schultz et al, ; Sepulcre et al, ). We speculate that tau alone acts in a protective manner against early neuronal injury.…”

“…Recent advances in neuroimaging have enabled investigation of brain networks using functional and structural magnetic resonance imaging (MRI) including diffusion tensor imaging (DTI; Achard & Bullmore, ; Gong et al, ; Iturria‐Medina, Sotero, Canales‐Rodríguez, Alemán‐Gómez, & Melie‐García, ). Studies using resting‐state functional MRI have revealed connectivity changes associated with tau deposition in preclinical AD (Schultz et al, ; Sepulcre et al, ). Schultz et al () demonstrated increased connectivity with low neocortical tau deposition but decreased connectivity with elevated tau deposition, raising the possibility that increased connectivity might be a compensatory response.…”

Revolution of Resting-State Functional Neuroimaging Genetics in Alzheimer’s Disease

“…The dissimilarities previously described may reflect supplementary effects – either genetically mediated during brain neurodevelopment or caused by an early low degree of amyloid deposition not yet detectable by positron emission tomography (PET) scanning. Indeed, recent studies demonstrated significant associations between τ PET uptake or τ protein concentrations in CSF and alterations in functional connectivity [56,57]. Therefore, investigation of inter-systems dynamics is warranted, such as the interplay of the genetic, molecular, and functional associations is warranted.…”

“…To date, no published studies have identified effects of specific genotypes on functional connectivity patterns in patients with prodromal AD [52] or with mild cognitive impairment (MCI) due to AD [57], that is, MCI individuals with a positive core biomarker signature positive, who have a high likelihood of progressing to AD dementia within a few years.…”

Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis

“…Over the past decade, multimodal neuroimaging techniques have been used to unravel the impact of Tau and Aβ accumulation on both GM and WM pathology. Functional MRI (fMRI) studies show reduced activity of functional networks and connectivity (Sepulcre et al, 2017, Pereira et al, 2019, Son et al, 2017, while diffusion-weighted MRI (DWI) studies demonstrate impaired WM integrity in AD (Agosta et al, 2011, Acosta-Cabronero et al, 2010. To determine the WM properties, Tract-based spatial statistical (TBSS) analytical technique has been used over the years in various disease contexts.…”