Early Alzheimer’s brain atrophy in entorhinal cortex is associated with HSD11B1-cortisol axis in APOE4 carriers
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Background Entorhinal cortex (EC) atrophy, driven by tau pathology, is an early hallmark of Alzheimer’s disease (AD), preceding hippocampal degeneration. APOE4 , the strongest genetic risk factor for AD, is linked to increased tau accumulation and impaired Aβ clearance in the EC. However, the specific cellular factors associated with APOE4 that contribute to this selective vulnerability remain unclear. Methods Longitudinal brain imaging, plasma biomarkers, and genetic polymorphism data from mild cognitive impairment (MCI) participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed. Linear regression and genetic association analyses were conducted to identify factors associated with entorhinal cortex volume, with stratified analyses examining the influence of APOE4 genotype. Results Cortisol, α1-antichymotrypsin (AACT), and trefoil factor 3 (TFF3) were identified as potential contributors to EC volume changes. Elevated plasma cortisol levels were significantly associated with EC volume decline in APOE4 carriers with MCI (p = 0.0043) and predicted a faster progression from MCI to AD (p = 0.040), whereas no such association was observed in noncarriers. HSD11B1, an enzyme responsible for converting cortisone to cortisol, showed higher expression in the EC compared to the hippocampus. Genetic analysis identified two functional HSD11B1 variants (rs2282738 and rs2282739) associated with elevated cortisol levels and increased AD risk. Notably, rs2282738 was significantly linked to EC volume decline (p = 0.0494), while no significant association was observed in the hippocampus. Conclusion Our findings suggest that HSD11B1-mediated local cortisol activation may contribute to entorhinal cortex vulnerability in APOE4 carriers with MCI, potentially accelerating AD onset. Targeting HSD11B1 could represent a promising therapeutic strategy to mitigate EC atrophy and slow disease progression in APOE4 carriers.
