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.

Neurofilament light chain (NFL) has been recently introduced as a biomarker of early dementia. 18-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is a proxy for regional hypometabolism in Alzheimer disease (AD). Globally normalized 18F-FDG-PET values and levels of NFL and tau were obtained from 149 patients with mild cognitive impairment (MCI) from the baseline cohort of the Alzheimer’s Disease Neuroimaging Initiative database. We adopted a stepwise partial correlation model using plasma NFL, plasma tau, CSF NFL, and regional cerebral metabolic rate of glucose (CMRGlc) as main variables, and age, sex, and Alzheimer’s Disease Rating Scale (ADAS) as covariates. Significant regions were entered into a stepwise multiple regression analysis to investigate the independent correlation of each biomarker to baseline regional CMRGlc and its progression in patients with MCI. Higher baseline CSF NFL levels correlated with hypometabolism in bilateral precuneal and posterior cingulate cortex. After correction for age, sex, and ADAS score, plasma NFL levels correlated with hypometabolism in bilateral parahippocampal and middle temporal gyri. Cortical hypometabolism in bilateral parahippocampal gyri and right fusiform and middle temporal gyri was independently predicted by higher baseline plasma NFL levels in a multiple regression model. Plasma NFL promises to be an early biomarker of cortical hypometabolism in MCI and for MCI progression to AD.

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