Therapeutic implications of allopregnanolone in Alzheimer's related depression

Alzheimer's disease (AD) and depression share common neuropathological mechanisms, with neuroinflammation, mitochondrial dysfunction, and impaired neurosteroid signalling contributing to both conditions. Allopregnanolone (ALLO), a potent neurosteroid, plays a crucial role in modulating mood, cognition, and neuroprotection via its interaction with GABA-A receptors and its ability to promote neurogenesis. Emerging evidence suggests that ALLO levels are significantly altered in AD, correlating with cognitive decline and neuropsychiatric symptoms, including depression. This review explores the pathological connection between AD and depression, highlighting the role of ALLO in mitigating disease progression and depressive symptoms. Preclinical studies demonstrate ALLO's ability to enhance synaptic plasticity, reduce β-amyloid toxicity, and alleviate depressive-like behaviours in AD models. Additionally, clinical trials investigating ALLO's therapeutic potential in AD and depression have shown promising results, though challenges remain in optimizing dosing, delivery, and patient selection. As a neurosteroid with both neuroprotective and antidepressant properties, ALLO represents a novel therapeutic approach that could bridge the gap between neurodegeneration and mood disorders. This review discusses the current understanding of ALLO's mechanistic role, its altered levels in AD and depression, and its potential as a disease-modifying therapy. Furthermore, we evaluate preclinical and clinical evidence supporting ALLO's efficacy, along with its limitations and future therapeutic prospects. By integrating neurosteroid-based strategies into AD treatment paradigms, ALLO may offer a promising avenue for addressing both cognitive decline and neuropsychiatric symptoms in AD-induced depression.