Gray matter atrophy mediates the association between cerebral hypometabolism and cognitive impairment in Alzheimer’s disease
Abstract
Objective Alzheimer’s disease (AD) is characterized by amyloid deposition, brain hypometabolism, gray matter atrophy and cognitive decline, yet their causal interactions are poorly defined. This multimodal PET/MRI study explored regional gray matter volume (GMV) loss and glucose hypometabolism in AD patients, and clarified their correlations with distinct cognitive deficits alongside mediating pathways. Methods 134 probable dementia patients were split into AD and non-AD dementia cohorts based on 18F-AV45 PET amyloid-β (Aβ) load, all receiving structural MRI, 18F-FDG and 18F-AV45 PET scans. We compared intergroup GMV and metabolic discrepancies, analyzed imaging-cognition correlations adjusted for clinical and demographic confounders, and implemented mediation models to test whether GMV bridges cerebral metabolism and cognition. Results AD patients exhibited prominent regional GMV shrinkage and FDG hypometabolism in vulnerable brain regions relative to non-AD dementia subjects. Covariate-adjusted analyses linked both imaging biomarkers to domain-specific cognitive performance. Primary mediation analyses showed that regional GMV significantly mediated the associations between FDG metabolism and visuospatial, executive, and language function, accounting for 40.36, 35.60, and 49.99% of the total effects, respectively. Reverse mediation models identified only a weak indirect effect of right superior temporal gyrus metabolism on the association between right inferior parietal lobule GMV and visuospatial ability, accounting for 13.26% of the total effect. Moreover, after multiple-imputation sensitivity analyses, most indirect effects became unstable or nonsignificant, suggesting that the FDG metabolism–cognition association is predominantly direct, with limited evidence for GMV mediation. Conclusion Integrated PET/MRI revealed AD-related patterns of regional atrophy and hypometabolism. Overall, the association between cerebral metabolic dysfunction and cognitive impairment appeared to be predominantly direct, with limited evidence supporting a mediating role of regional GMV.