Functional connectivity density as a biomarker for Alzheimer's disease: Distinct neural mechanisms in young- and...

Alzheimer's disease (AD) shows distinct trajectories of cognitive decline based on age of onset, highlighting the need for reliable functional biomarkers.

This study aims to evaluate whether functional connectivity density (FCD) can serve as a functional biomarker linking tau pathology to cognition, either directly or as a mediator.

We included 52 cognitively unimpaired controls, 54 late-onset AD (LOAD), and 44 young-onset AD (YOAD) patients who underwent amyloid and [F18]Florzolotau PET, resting-state functional magnetic resonance imaging (MRI), and two cognitive tests. Voxel-wise FCD analyses compared patient groups with controls. Direct associations between FCD and cognition were assessed, and mediation analyses tested whether FCD mediated tau-related cognitive effects.

In YOAD, reduced precuneus short-range FCD was directly associated with poorer cross-sectional cognitive performance, without mediating or moderating longitudinal decline. In LOAD, higher left anterior cingulate FCD covaried with tau burden and fully mediated its relationship with cognition and the rate of decline.

Our results reveal distinct FCD signatures in YOAD and LOAD that mirror their differential functional responses to tau pathology. In YOAD, reduced precuneus FCD appears to serve as a state marker of cognitive impairment, whereas in LOAD, elevated anterior cingulate FCD suggests compensatory network recruitment consistent with a functional reserve model. These findings underscore FCD's promise as a subtype-specific biomarker for tracking AD progression.