Abstract
Neurodegeneration is presumed to be the pathological process measure most proximal to clinical symptom onset in Alzheimer Disease (AD). Structural MRI is routinely collected in research and clinical trial settings. Several quantitative MRI-based measures of atrophy have been proposed, but their low correspondence with each other has been previously documented. The purpose of this study was to identify which commonly used structural MRI measure (hippocampal volume, cortical thickness in AD signature regions, or brain age gap [BAG]) had the best correspondence with the Clinical Dementia Rating (CDR) in an ethno-racially diverse sample. 2870 individuals recruited by the Healthy and Aging Brain Study-Health Disparities completed both structural MRI and CDR evaluation. Of these, 1887 individuals were matched on ethno-racial identity (Mexican American [MA], non-Hispanic Black [NHB], and non-Hispanic White [NHW]) and CDR (27% CDR > 0). We estimated brain age using two pipelines (DeepBrainNet, BrainAgeR) and then calculated BAG as the difference between the estimated brain age and chronological age. We also quantified their hippocampal volumes using HippoDeep and cortical thicknesses (both an AD-specific signature and average whole brain) using FreeSurfer. We used ordinal regression to evaluate associations between neuroimaging measures and CDR and to test whether these associations differed between ethno-racial groups. Higher BAG (p(DeepBrainNet) = 0.0002; p(BrainAgeR) = 0.00117) and lower hippocampal volume (p = 0.0015) and cortical thickness (p < 0.0001) were associated with worse clinical status (higher CDR). AD signature cortical thickness had the strongest relationship with CDR (AIC(DeepBrainNet) = 2623, AIC(whole cortex) = 2588, AIC(BrainAgeR) = 2533, AIC(Hippocampus) = 2293, AIC(Signature Cortical Thickness) = 1903). The relationship between CDR and atrophy measures differed between ethno-racial groups for both BAG estimates and hippocampal volume, but not for cortical thickness. We interpret the lack of an interaction between ethno-racial identity and AD signature cortical thickness on CDR as evidence that cortical thickness effectively captures sources of disease-related atrophy that may differ across racial and ethnic groups. Cortical thickness had the strongest association with CDR. These results suggest that cortical thickness may be a more sensitive and generalizable marker of neurodegeneration than hippocampal volume or BAG in ethno-racially diverse cohorts.