Delineating the Heterogeneity of Alzheimer's Disease and Mild Cognitive Impairment Using Normative Models of Dynamic Brain Functional Networks

Alzheimer's disease (AD), which has been identified as the most common type of dementia, presents considerable heterogeneity in its clinical manifestations. Early intervention at the stage of mild cognitive impairment (MCI) holds potential in AD prevention. However, characterizing the heterogeneity of neurobiological abnormalities and identifying MCI subtypes pose significant challenges.

We constructed sex-specific normative age models of dynamic brain functional networks and mapped the deviations of the brain characteristics for individuals from multiple datasets, including 295 patients with AD, 441 patients with MCI, and 1160 normal control participants. Then, based on these individual deviation patterns, subtypes for both AD and MCI were identified using the clustering method, and their similarities and differences were comprehensively assessed.

Individuals with AD and MCI were clustered into 2 subtypes, and these subtypes exhibited significant differences in their intrinsic brain functional phenotypes and spatial atrophy patterns, as well as in disease progression and cognitive decline trajectories. The subtypes with positive deviations in AD and MCI shared similar deviation patterns, as did those with negative deviations. There was a potential transformation of MCI with negative deviation patterns into AD, and participants with MCI had a more severe cognitive decline rate.

In this study, we quantified neurophysiological heterogeneity by analyzing deviation patterns from the dynamic functional connectome normative model and identified disease subtypes of AD and MCI using a comprehensive resting-state functional magnetic resonance imaging multicenter dataset. The findings provide new insights for developing early prevention and personalized treatment strategies for AD.