Multiple target strategies in Alzheimer’s disease therapy

The paradigm for treating Alzheimer’s disease (AD) has begun to evolve in the presence of clinical inefficacy and safety concerns of antibody-based β amyloid (A β ) reduction strategies. The AD treatment strategy is moving toward with multi-target approaches that address interconnected pathological processes. The central lymphatic system, including the glymphatic and meningeal lymphatic systems, has been an emerging target for clearance of A β /tau through its drainage function. Neuroinflammation, lipid disorders, brain insulin resistance, loss of neural stem cells and gut–brain axis represent additional therapeutic targets. Simultaneous modulation of these pathways offers an avenue for the next-generation of AD therapy. Here we integrate multidiscipline evidence to support the paradigm shift and propose future directions, which encompass pharmacological, physical ( e . g ., 40 Hz stimulation, exercise), and surgical interventions ( e . g ., deep cervical lymphovenous anastomosis) of these pathways. Challenges regarding application of these strategies are presented with a call for biomarker-guided patient stratification, new trial designs, and establishment of regulatory guidelines.