Macro-Scale Cortical Thickness Homogeneity in Alzheimer’s Disease: A Multi-Cohort Analysis of 11,382 Structural MRI Scans

Background Alzheimer’s disease (AD) is characterized by progressive, regionally heterogeneous cortical atrophy. Whether whole-brain cortical thickness homogeneity serves as an informative macro-scale marker of this structural disruption remains unclear. This study evaluated cortical thickness homogeneity across a large, multi-cohort sample and assessed its independent diagnostic utility. Methods Structural MRI data comprising 11,382 scans from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Open Access Series of Imaging Studies 3 (OASIS-3) were analyzed. Cortical thickness was extracted across 68 Desikan-Killiany regions. A cortical thickness homogeneity index-defined as the mean pairwise similarity of absolute regional thickness differences-was computed from within-dataset Z-scored values. Linear mixed-effects models with random intercepts for participant ID, adjusted for age and sex, compared diagnostic groups. Logistic regression evaluated added diagnostic value beyond medial temporal lobe (MTL) thickness. Statistical path decomposition evaluated the contribution of MTL atrophy. Results Dementia patients exhibited significantly lower cortical homogeneity than controls (total effect β = −0.035; LME-adjusted β = −0.029, Cohen's d = 0.95, p < 0.001), independent of age and sex. The effect was regionally specific to the temporal lobe. The baseline diagnostic model (MTL thickness, age, sex) achieved an area under the curve (AUC) of 0.738 on external validation. Adding cortical homogeneity yielded an AUC of 0.746, a non-significant improvement (DeLong’s test, p = 0.198). Statistical path decomposition showed that MTL atrophy statistically accounted for 31.5% of the association between diagnosis and whole-brain homogeneity. Conclusion Cortical thickness homogeneity captures macro-scale structural degradation in AD but functions primarily as a downstream proxy of regional temporal atrophy and does not improve diagnostic accuracy beyond standard regional measures.