A Systematic Review of the Association between Amyloid-β and τ Pathology with Functional Connectivity Alterations in the Alzheimer Dementia Spectrum Utilizing PET Scan and rsfMRI

The association between functional connectivity (FC) alterations with amyloid-β (Aβ) and τ protein depositions in Alzheimer dementia is a subject of debate in the current literature. Although many studies have suggested a declining FC accompanying increased Aβ and τ concentrations, some investigations have contradicted this hypothesis. Therefore, this systematic review was conducted to sum up the current literature in this regard. The PROSPERO guideline for systematic reviews was applied for development of a research protocol, and this study was initiated after getting the protocol approval. Studies were screened, and those investigating FC measured by resting-state functional MRI and Aβ and τ protein depositions using amyloid and τ positron emission tomography were included. We categorized the included studies into 3 groups methodologically, addressing the question using global connectivity analysis (examining all regions of interest across the brain based on a functional atlas), seed-based connectivity analysis, or within-networks connectivity analysis. The quality of the studies was assessed using the Newcastle-Ottawa Scale. Among 31 included studies, 14 found both positive and negative correlations depending on the brain region and stage of the investigated disease, while 7 showed an overall negative correlation, 8 indicated an overall positive correlation, and 2 found a nonsignificant association between protein deposition and FC. The investigated regions were illustrated using tables. The posterior default mode network, one of the first regions of amyloid accumulation, and the temporal lobe, the early τ deposition region, are the 2 most investigated regions where inconsistencies exist. In conclusion, our study indicates that transneuronal spreading of τ and the amyloid hypothesis can justify higher FC related to higher protein depositions when global connectivity analysis is applied. However, the discrepancies observed when investigating the brain locally could be due to the varying manifestations of the amyloid and τ overload compensatory mechanisms in the brain at different stages of the disease with hyper- and hypoconnectivity cycles that can occur repeatedly. Nevertheless, further studies investigating both amyloid and τ deposition simultaneously while considering the stage of Alzheimer dementia are required to assess the accuracy of this hypothesis.