Targeting immunometabolic pathways for combination therapy in Alzheimer's disease

The recent success of disease‐modifying anti‐amyloid monoclonal antibodies in slowing Alzheimer's disease (AD) symptoms has been an exciting step forward for the field. Despite successfully clearing amyloid from the brain, however, only modest symptomatic improvement has been demonstrated, and treatment‐related side effects such as amyloid‐related imaging abnormalities (ARIA) limit use for some. These limitations suggest that fully efficacious AD treatment may require combination therapy regimens, as are used in other complex disorders such as cancer and HIV. One reasonable strategy may be to use agents that address the biological changes that predict future amyloid accumulation, or accompany amyloid accumulation in preclinical disease states. Immunometabolic pathways, including the insulin signaling pathway, are dysregulated at the earliest stages of AD, concomitant with amyloid accumulation. It is plausible that agents that target these pathways may work synergistically with anti‐amyloid therapies to halt AD progression. Insulin signaling is integrally involved in innate and adaptive immune systems, with pleiotropic effects that moderate pro‐ and anti‐inflammatory responses. Metabolic modulators that enhance insulin sensitivity and function, such as GLP‐1 receptor agonists, SGLT2 inhibitors, and insulin itself have been shown to improve immune function and reduce chronic inflammation. Additional effects of insulin and metabolic modulators demonstrated in preclinical and clinical studies of AD include increased clearance of amyloid‐β, slowed tau progression, improved vascular function and lipid metabolism, reduced synaptotoxicity, and improved cognitive and functional outcomes. A large number of compounds that treat metabolic disorders have been extensively characterized with respect to mechanism of action and safety, and thus are readily available to be repurposed for combination therapy protocols. Determining the most successful combination regimens of these agents together with disease‐modifying therapies, and the appropriate timing of treatment, are promising next steps in the quest to treat and prevent AD.