Stage-dependent associations of plasma clusterin with reduced brain volume, tau pathology, and cognitive impairment across the Alzheimer's disease spectrum.

Clusterin, a multifunctional glycoprotein involved in proteostasis, amyloid-β clearance, and neuroinflammation, has been proposed as a biomarker in Alzheimer's disease (AD), but its stage-specific links to brain structure, tau pathology, and cognition remain unclear. This study evaluated plasma clusterin across the AD spectrum, its associations with brain volumes and CSF tau/p-tau, and whether structural brain measures mediate its cognitive effects. Data from 333 participants (CN = 38, MCI = 207, AD = 88) were analyzed using FDR-corrected regression, Pearson correlations, and mediation analyses, adjusting for demographic factors and APOE ɛ4 status. Results showed that plasma clusterin was highest in mild cognitive impairment (MCI) compared to cognitively normal (CN) and AD, suggesting a peak during early neurodegeneration. In CN participants, higher clusterin was associated with lower whole-brain volume, but it was not significantly related to hippocampal volumes or tau/p-tau. In MCI, clusterin was modestly associated with reduced whole-brain volume and elevated CSF tau, while associations with hippocampal volumes and p-tau were nonsignificant. In AD, higher clusterin was significantly associated with smaller left and right hippocampal volumes, with a trend toward lower whole-brain volume; no significant associations with tau or p-tau were observed. Based on the mediation analysis, in CN participants, no significant mediation effects of brain volumes were observed between plasma clusterin and cognitive function. In the MCI group, higher plasma clusterin was associated with lower whole-brain volume, and this volumetric measure showed significant indirect effects linking plasma clusterin to cognitive performance, consistent with indirect-only (full mediation) patterns. This suggests an indirect association whereby higher clusterin may be linked to poorer cognitive function through its association with reduced global brain volume. Likewise, in the AD group, higher clusterin levels were associated with lower whole-brain and right hippocampal volumes. Both measures significantly mediated the relationship between clusterin and cognitive performance, indicating that higher clusterin may be linked to poorer cognitive function through its association with reductions in global and region-specific brain volumes. Future studies should clarify the temporal and mechanistic pathways linking clusterin to neurodegeneration to determine its value as a biomarker and therapeutic target.