Redirecting Alzheimer's disease therapeutics: Multitarget drugs and complementary non-pharmacological strategies

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder driven by intersecting pathological processes. Persistent attrition in AD drug-development pipelines highlights the limited clinical impact of single-target therapies and has increased interest in multi-target approaches acting on shared biological hubs. Although recent strategies extend beyond amyloid-centered interventions, much of the evidence supporting multifunctional compounds remains preclinical or shows heterogeneous outcomes in advanced clinical stages. This narrative review examines drug candidates that have entered Phase III clinical trials in the last decade, with emphasis on emerging multitarget pharmacotherapies such as muscarinic M1 receptor agonists, dual M1/sigma-1 receptor (σ1R) agonists, and dual σ1R agonist/anti-amyloid agents. We also discuss complementary non-pharmacological interventions, including physical exercise and targeted nutrition, that may support cognitive and emotional outcomes. Finally, we propose the Synergistic Optimized Pharmacological and Holistic Interventions for AD (SOPHI-AD) framework as a conceptual and testable approach integrating multitarget pharmacology with lifestyle-based strategies for AD management.