EXPRESS: Synaptic density PET mediates the relationship between Alzheimer's disease pathology and cognitive performance.

INTRODUCTION Synaptic loss is one of the strongest post-mortem predictors of Alzheimer's disease (AD) severity and may impact how pathology affects cognition. This study compared regional [11C]UCB-J synaptic density across the AD continuum and evaluated the extent to which synaptic density mediates relationships between AD biomarkers.

Methods

Seventy-two participants completed PET scans, MRIs, and cognitive testing. Participants were categorized into subgroups representing typical AD progression. Regional synaptic density was compared across subgroups and pathological variables. Standard mediation and moderated mediation analyses were performed using amyloid and tau as predictors/moderators and MoCA score as outcome.

Results

The amyloid+/tau+/impaired subgroup showed lower synaptic density than controls, particularly for transverse temporal, inferior parietal, and hippocampal regions (Cohen's d=1.60, 1.57, 1.50). Hippocampal synaptic density had the strongest associations with tau (β=-0.473); transverse temporal synaptic density had the strongest association with amyloid (β=-0.543) and age (β=-0.614). Eight of twelve assessed brain regions demonstrated significant indirect effects across mediation frameworks. The inferior parietal lobe showed the largest mediation for amyloid (45.3%) and tau (28.9%).

Discussion

These findings support the hypothesis that synaptic loss is a primary mechanism contributing to clinical AD and suggest that synaptic density imaging can provide complementary information to the existing AD framework.