Immunotherapy of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Despite continuous research using biomarkers to identify pathogenic mechanisms, a complete understanding of the disease-related processes is far from being achieved. Consequently, effective disease-modifying therapies are still lacking. Several therapeutic strategies have been tested in clinical trials for AD. Misfolded protein aggregates formed by amyloid-β and tau proteins represent the pathological hallmarks of AD and are associated with synapsis alteration and neuronal loss. This evidence led to the amyloid cascade hypothesis, in which amyloid- β and tau accumulation are strictly related and associated with progressive neurodegeneration. Immunotherapeutic approaches targeting amyloid-β and tau proteins showed promising effectiveness in preclinical studies. However, clinical trial results are disappointing. The failure of clinical trials on vaccines and humanized anti-amyloid-β and anti-tau monoclonal antibodies has questioned the strength of the amyloid hypothesis. The Aducanumab, recently approved by the United States Food and Drug Administration, is an anti-amyloid-β monoclonal antibody showing a beneficial effect in AD patients. However, its use has been debated due to the negligible clinical improvement compared with the pathology resolution. Immunotherapies targeting tau, microglia, and the gut-brain axis are under development, but further research is still required to clarify the exact benefit of these approaches. The current chapter will provide an overview of the immunotherapeutic approaches studied or in use. We will focus on amyloid-β, tau, and microglia in AD, discussing future perspectives on immunotherapies in AD.