Therapeutic Targeting of the α7 Nicotinic Receptor: Challenges and Prospects for Cognitive Improvement in Alzheimer's and Schizophrenia

The α7 nicotinic acetylcholine receptor (α7 nAChR) has emerged as a key target for treating cognitive dysfunction in neurological disorders such as Alzheimer's disease (AD) and schizophrenia. α7 nAChRs play essential roles in neurotransmission, neuroinflammation and synaptic plasticity, not only in neurons but also in glial cells, where they engage in metabotropic signalling. Despite promising preclinical findings, clinical trials of α7 nAChR agonists, partial agonists and positive allosteric modulators (PAMs) have yielded inconsistent results, with few achieving sustained cognitive benefits in patients. This review examines the functional properties of α7 nAChRs, ionotropic and metabotropic signalling roles, and their contribution to cognitive processes in AD and schizophrenia. We provide a comprehensive analysis of key α7-targeted compounds that advanced to clinical trials, detailing their outcomes and challenges. Additionally, we discuss major translational barriers, including receptor desensitization, pharmacokinetic limitations, inter-individual variability (e.g., effects of smoking on metabolism) and species differences in preclinical models. Finally, we explore innovative strategies to improve trial success, including optimized dosing regimens, co-administration with PAMs and neuroimaging techniques like PET to refine patient selection and drug evaluation. These approaches may offer a more effective pathway for developing α7-targeted cognitive therapies in AD and schizophrenia.