Medial Temporal Atrophy and Posterior Cingulate Structural Covariance in Mild Cognitive Impairment

BACKGROUND: Mild cognitive impairment (MCI) is associated with structural abnormalities in regions vulnerable to Alzheimer's disease, but the relative contributions of medial temporal, posterior midline, and association cortices remain unclear. We compared regional gray matter volumes between individuals with MCI and cognitively normal (CN) participants and examined their associations with clinical measures, structural covariance, and apolipoprotein E ε4 (APOE ε4) status. METHODS: We analyzed 264 participants from the Alzheimer's Disease Neuroimaging Initiative. Gray matter volumes were extracted from seven predefined regions of interest. Group differences and clinical associations were assessed using multivariable regression models adjusted for age, sex, education, and total intracranial volume. Structural covariance analyses examined interregional relationships. Exploratory analyses evaluated ROI-by-APOE ε4 interactions, and sensitivity analyses assessed robustness. RESULTS: Individuals with MCI had smaller hippocampal volumes than CN participants, whereas parahippocampal reductions were less consistent. Smaller hippocampal volume was consistently associated with greater cognitive impairment and poorer functional performance; associations involving the parahippocampal gyrus weakened after adjustment for hippocampal volume. The posterior cingulate cortex showed limited evidence of local volumetric differences but more prominent alterations in structural covariance with medial temporal and temporal association regions. Exploratory APOE ε4 interactions were nominally suggestive but did not survive multiple-comparison correction. Main findings were generally robust across sensitivity analyses. CONCLUSIONS: Hippocampal volume showed the most consistent local volumetric and clinical associations in MCI, whereas posterior cingulate abnormalities were more evident in structural covariance patterns. Regional atrophy and altered interregional structural covariance may provide complementary information about brain structural changes in MCI.