👤 Laxmidhar Maharana

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. Show less

Sex hormone-binding globulin (SHBG), which regulates androgen and estrogen bioavailability, has been linked to cognitive decline, but its relationship with temporal lobe changes-an area vulnerable in early Alzheimer's disease (AD)-remains unclear. This study aimed to investigate whether plasma SHBG levels are associated with temporal lobe volume and cognitive performance across the cognitive spectrum from normal aging to AD. Participants included individuals with AD (n = 85), mild cognitive impairment (MCI; n = 304), and cognitively normal controls (CN; n = 50). Cognitive performance was assessed using the ADAS-Cog 11, MMSE, and CDR-SB. Temporal lobe volumes were derived from MRI scans using tensor-based morphometry (TBM), and plasma SHBG levels were measured using a validated immunoassay. Multiple regression analyses adjusted for age, sex, education, handedness, and APOE ε4 status were conducted, followed by mediation analysis to test indirect effects through temporal lobe volume. After covariate adjustment, elevated plasma SHBG levels were significantly associated with reduced temporal lobe volume in the MCI group. Across both MCI and AD participants, greater temporal lobe volume correlated with better cognitive performance on all tests. Mediation analysis indicated that in MCI, the relationship between higher plasma SHBG and poorer cognitive outcomes was significantly mediated by reduced temporal lobe volume. These findings suggest that elevated SHBG may contribute to early cognitive impairment in MCI through its impact on temporal lobe integrity, highlighting SHBG as a potential target in the prodromal stages of AD. Show less