Emerging and Repurposed Immune System Modulators for Alzheimer's Disease

Alzheimer's disease (AD) remains an incurable neurodegenerative condition to date. Pathologically, the hallmarks of AD are (i) extracellular senile plaques mainly composed of amyloid beta peptides (Aβ), (ii) intracellular neurofibrillary tangles comprised of abnormally folded and hyperphosphorylated tau proteins, and (iii) neuroinflammation. In the past two decades, the investigation of these brain pathologies has led to the identification of novel diagnostic biomarkers and putative therapeutic targets, ultimately resulting in the first two commercial disease-modifying anti-Aβ immunotherapies. More recently, modulation of the overactivated central immune system has emerged as a unique putative approach to slow down the progression of AD. In the present narrative review, we summarize the main findings on modulators of inflammation tested in Phase 2 and 3 trials in AD patients. After a deep literature review, we ended up selecting 19 agents spanning immune primers, monoclonal antibodies, recombinant proteins, synthetic peptides, immunomodulatory drugs, ion channel blockers, tyrosine kinase inhibitors, senolytics, antivirals, and herbal formulations. For each agent, we briefly explain the preclinical findings that led to translation into clinical trials and provide details about each trial design, and, when available, the main findings from the trials. Overall, it appears that Aβ and abnormal tau activate both the innate and adaptive immune systems, which in turn galvanize the production of Aβ and abnormal tau, thereby forming a viscous cycle that inflates AD neuropathology and is difficult to interrupt. Based on the successes and failures of the 19 agents reported here, we postulate that immune system modulators with the strongest potential for AD treatment are those displaying pleiotropic actions on both innate and adaptive immune responses rather than those exhibiting very targeted mechanisms. We conclude that modulators of inflammation need to be studied further, both as stand-alone AD therapies and in combination with anti-amyloid and anti-tau approaches.