Prediction of Cognitive Progression Due to Alzheimer's Disease in Normal Participants Based on Individual Default Mode Network Metabolic Connectivity Strength

Abstract

Background: Predicting cognitive decline among individuals in the aging population who are already amyloid-β (Aβ) positive or tau positive poses clinical challenges. In Alzheimer's disease research, intra-default mode network (DMN) connections play a pivotal role in diagnosis. In this article, we propose metabolic connectivity within the DMN as a supplementary biomarker to the Aβ, pathological tau, and neurodegeneration framework.

Methods: Extracting data from 1292 participants in the Alzheimer's Disease Neuroimaging Initiative, we collected paired T1-weighted structural magnetic resonance imaging and ¹⁸F-labeled-fluorodeoxyglucose positron emission computed tomography scans. Individual metabolic DMN networks were constructed, and metabolic connectivity (MC) strength in the DMN was assessed. In the cognitively unimpaired group, the Cox model identified cognitively unimpaired (MC+), high-risk participants, with Kaplan-Meier survival analyses and hazard ratios revealing the strength of MC's predictive performance. Spearman correlation analyses explored relationships between MC strength, and Aβ, pathological tau, neurodegeneration biomarkers, and clinical scales. DMN standard uptake value ratio (SUVR) provided comparative insights in the analyses.

Results: Both MC strength and SUVR exhibited gradual declines with cognitive deterioration, displaying significant intergroup differences. Survival analyses indicated enhanced Aβ and tau prediction with both metrics, with MC strength outperforming SUVR. Combined MC strength and Aβ yielded optimal predictive performance (hazard ratio = 9.29), followed by MC strength and tau (hazard ratio = 8.92). Generally, the strength of MC's correlations with Aβ, pathological tau, and neurodegeneration biomarkers exceeded SUVR.

Conclusions: Individuals with normal cognition and disrupted DMN metabolic connectivity face an elevated risk of cognitive decline linked to Aβ that precedes metabolic issues.

Keywords: (18)F-FDG PET; Alzheimer’s disease; Cognitive decline; Cognitively unimpaired; Default mode network; Metabolic connectivity.