biostudies-literatureUnknown16(8)Lai RRationale: 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 apolipoprotein E ε4 (APOE4) carriers in preclinical studies, despite evidence that APOE4 alters stress responses and glucocorticoid regulation. We hypothesized that APOE4 status modulates the efficacy of HSD11B1 inhibition by influencing cortisol metabolism and AD pathology. Methods: We conducted a genetic association study to test whether HSD11B1 variants are linked to Theranostics4113-4127https://www.ebi.ac.uk/biostudies/studies/S-EPMC12905795biostudies-literatureWhy 11β-HSD1 inhibitors show variable efficacy in Alzheimer's therapy: an APOE4-dependent HSD11B1 mechanism.PMC12905795Chung RJuang JLai RShie FHsu PWChen YLam KfalseWhy 11β-HSD1 inhibitors show variable efficacy in Alzheimer's therapy: an APOE4-dependent HSD11B1 mechanism.Rationale: 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 apolipoprotein E ε4 (APOE4) carriers in preclinical studies, despite evidence that APOE4 alters stress responses and glucocorticoid regulation. We hypothesized that APOE4 status modulates the efficacy of HSD11B1 inhibition by influencing cortisol metabolism and AD pathology. Methods: We conducted a genetic association study to test whether HSD11B1 variants are linked to 2026-01-01T00:00:00Z20262026-07-16T00:08:43.925Z2026-07-09T10:26:00.373ZS-EPMC129057954169549010.7150/thno.126244