Why 11β-HSD1 inhibitors show variable efficacy in Alzheimer's therapy: an APOE4-dependent HSD11B1 mechanism

<b>Rationale:</b> Clinical trials for Alzheimer's disease (AD) often yield inconsistent results despite promising preclinical findings. Inhibition of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), a cortisone reductase, has demonstrated neuroprotective effects in preclinical models. However, clinical outcomes have varied. A potential explanation is the limited representation of <i>apolipoprotein E ε4</i> (<i>APOE4</i>) carriers in preclinical studies, despite evidence that <i>APOE4</i> alters stress responses and glucocorticoid regulation. We hypothesized that <i>APOE4</i> status modulates the efficacy of HSD11B1 inhibition by influencing cortisol metabolism and AD pathology. <b>Methods:</b> We conducted a genetic association study to test whether <i>HSD11B1</i> variants are linked to plasma cortisol levels, brain atrophy, and AD risk, stratified by <i>APOE4</i> status. Postmortem human brain tissues and wild-type mice were analyzed for <i>HSD11B1</i> expression, with emphasis on the entorhinal cortex (EC). Neuroimaging data were examined to assess correlations between cortisol levels and brain volume. In cell models, recombinant APOE4 protein was tested for regulation of <i>HSD11B1</i> expression via the transcription factor C/EBPβ and its effect on neuronal cortisol production. <b>Results:</b> We identified a functional <i>HSD11B1</i> variant associated with elevated cortisol, increased AD risk, and accelerated EC atrophy, specifically in <i>APOE4</i> carriers. <i>HSD11B1</i> was significantly upregulated in the EC of <i>APOE4</i>-positive brains. Mechanistic studies demonstrated that APOE4, but not APOE3, upregulates <i>HSD11B1</i> via C/EBPβ, thereby increasing neuronal cortisol. <b>Conclusions:</b> These findings explain the inconsistent efficacy of 11β-HSD1 inhibitors in AD patients by revealing an APOE4-dependent activation of HSD11B1 that promotes early EC pathology. They also support genotype-guided therapeutic strategies targeting local cortisol metabolism.