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

Abstract

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.

Unravelling the relationship between amyloid accumulation and brain network function in normal aging and very mild cognitive decline: a longitudinal analysis

“…Previous research suggests that Aβ plaque accumulation in preclinical Alzheimer’s disease may have functional correlates. 19 , 39–41 When focusing on amyloid and functional connectivities in regions with faster rates of change in progressors than non-progressors, we also found that rates of amyloid accumulation were correlated with rates of change in FC. Our results contribute to the understanding of amyloid staging in the earliest phases of preclinical Alzheimer’s disease and show that changes across a number of functional brain networks are linked to amyloid accumulation.…”

“…Moreover, hyperconnectivity between functional networks would help facilitate Aβ spread as FC changes precede Aβ accumulation 11 , 49 and functional networks have been shown to facilitate tau spread. 19 , 55 , 56 …”

“… 18 Thus, the direction of functional connectivity (FC) changes may fluctuate throughout the course of disease progression. 19 A more comprehensive understanding of functional changes and the timeline at which they occur is needed. Additionally, changes in other brain areas related to executive function and higher cognitive abilities have also been implicated in Alzheimer’s disease, as well as normal aging, including the frontoparietal network (FPN) and cingulo-opercular network.…”

Impact of APOE ε4 Carrier Status on Associations Between Subthreshold, Positive Amyloid-β Deposition, Brain Function, and Cognitive Performance in Cognitively Normal Older Adults: A Prospective Study

“…Moreover, considering the results of previous studies showing that Aβ changes rather than that baseline accumulation predicts prospective cognitive change (Farrell et al, 2018 ); accordingly, it is necessary to conduct a longitudinal study for a clear interpretation of the results of the current study. Given that prior study has demonstrated an interaction between Aβ and tau for changes in the FC of the CN (Hasani et al, 2021 ), another issue with this study is the lack of information on the tau deposits. Additionally, it has been reported that the FMM has a relatively low sensitivity to diffuse plaques that are usually detected in the earliest phase of Aβ accumulation (Salloway et al, 2017 ).…”

Assessment of Neurodegenerative Changes in Turkeys Fed Diets with Different Proportions of Arginine and Methionine Relative to Lysine

“…Both a deficiency of acetylcholinesterase and the formation of complexes of this enzyme with amyloid-β (glycosylated acetylcholinesterase, GAChE) are conducive to mitochondrial dysfunction and the generation of large amounts of reactive oxygen species, which initiate neuronal apoptosis [ 24 , 25 , 26 , 27 ]. Moreover, it may be useful to determine the level of low-density lipoprotein receptor-related protein 1 (LRP1), which facilitates the degradation of toxic amyloid-β [ 28 ]. Evaluation of the degree of methylation of histone proteins, resulting from the covalent modifications of lysine and arginine residues, may also be helpful in recognizing the intensification of neurodegenerative changes [ 29 ].…”