Functional Connectome Alterations Across the Spectrum of Alzheimer’s Disease

Alzheimer’s disease (AD) pathology is marked by the deposition of amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles. This pathology begins years before the first clinical symptoms emerge and progresses through several stages before clinical diagnosis. AD’s pathology alters the brain’s functional connectivity (FC) patterns and these altered FC patterns may serve as imaging markers to diagnose and assess the progression of AD. In this review, we summarize the recent literature investigating connectome alterations across the AD spectrum, spanning preclinical, prodromal, and clinical stages. We identify specific regions and functional connections that are altered across different stages of AD and discuss their relevance to cognition. We also highlight the potential of connectome-based predictive modeling as an individual-specific method in the quest for early diagnosis of AD. The default mode network (DMN) shows significant changes across stages, and its core hubs consistently exhibit reduced connectivity with the medial temporal lobe in association with disease pathology. From a dynamic FC point of view, the flexibility of different networks, especially DMN, was reduced as a result of AD onset and persisted across the stages. These disruptions were also linked to reduced cognitive performance, particularly in domains such as memory and executive function. By bringing together evidence on both disease-specific and stage-specific alterations in FC, this review aims to identify patterns that are most informative for understanding AD progression and their potential for advancing early diagnosis.