Amyloid-Beta Influences Memory via Functional Connectivity During Memory Retrieval in Alzheimer's Disease

Objective: Amnesia in Alzheimer's disease (AD) appears early and could be caused by encoding deficiency, consolidation dysfunction, and/or impairment in the retrieval of stored memory information. The relationship between AD pathology biomarker β-amyloid and memory dysfunction is unclear. Method: The memory task functional MRI and amyloid PET were simultaneously performed to investigate the relationship between memory performance, memory phase-related functional connectivity, and cortical β-amyloid deposition. We clustered functional networks during memory maintenance and compared network connectivity between groups in each memory phase. Mediation analysis was performed to investigate the mediator between β-amyloid and related cognitive performance. Results: Alzheimer's disease was primarily characterized by decreased functional connectivity in a data-driven network composed of an a priori default mode network, limbic network, and frontoparietal network during the memory maintenance (0.205 vs. 0.236, p = 0.04) and retrieval phase (0.159 vs. 0.183, p = 0.017). Within the network, AD had more regions with reduced connectivity during the retrieval than the maintenance and encoding phases (chi-square p = 0.01 and < 0.001). Furthermore, the global cortical β-amyloid negatively correlated with network connectivity during the memory retrieval phase (R = – 0.247, p = 0.032), with this relationship mediating the effect of cortical β-amyloid on memory performance (average causal mediation effect = – 0.05, p = 0.035). Conclusion: We demonstrated that AD had decreased connectivity in specific networks during the memory retrieval phase. Impaired functional connectivity during memory retrieval mediated the adverse effect of β-amyloid on memory. These findings help to elucidate the involvement of cortical β-amyloid (Aβ) in the memory performance in the early stages of AD.