Recent advances in Alzheimer’s disease pathogenesis and therapeutics from an immune perspective

Abstract

Background: The prevalence of Alzheimer’s disease, the most common type of dementia, is continuously increasing. Many recent reports have indicated that immune-related mechanisms play a vital role in Alzheimer’s disease pathogenesis, such that the imbalance between the immune response and central nervous system leads to neuroinflammation.

Area covered: The inflammatory response in Alzheimer’s disease is a “double-edged sword”. Neuroinflammation protects neuronal cells in the initial stages of Alzheimer’s disease, while sustained inflammation promotes neurodegeneration. Alterations in the peripheral immune system, such as increased inflammation, lead to the activation of the central immune response, which in turn causes neuroinflammation and neuronal damage. Additionally, an imbalance between pro- and anti-inflammatory cytokines, which are secreted by the central and peripheral immune systems, induces complex immune responses and contributes to Alzheimer’s disease pathogenesis. In this review, we aimed to summarize our current knowledge of the role of the immune system in Alzheimer’s disease pathology. We performed an in-depth investigation on the contribution of each immune system component to Alzheimer’s disease progression at different disease stages. More importantly, we discuss novel immune-related therapeutic strategies for Alzheimer’s disease treatment currently being investigated via clinical trials.

Expert opinion: The scrutinized observations of immune responses in different brain regions at various stages of Alzheimer’s disease might help identify potential treatment strategies for Alzheimer’s disease. The modulation of immune components in the brain by targeting cytokines and other factors, which compromise immune response and neuroinflammation, is recommended as a promising alternative for Alzheimer’s disease treatment. Clinical trials are currently investigating the efficacies of numerous vaccines and monoclonal antibodies targeting amyloid beta peptide and tau protein for Alzheimer’s disease treatment. Moreover, aducanumab and lecanemab were approved by the Food and Drug Administration as monoclonal antibody-based drugs for Alzheimer’s disease treatment in 2021 and 2023, respectively. However, these drugs are effective only against mild symptoms due to the irreversible neuronal damage found in patients with Alzheimer’s disease progression. In addition, side effects including amyloid-related imaging abnormalities (such as vasogenic edema, microhemorrhages, and hemosiderosis) were reported in patients undergoing Alzheimer’s disease treatment using monoclonal antibodies. Thus, the future development of therapeutic agents for Alzheimer’s disease requires more sophisticated and multi-plunged approaches considering various biomarkers and immune landscapes characterizing the different stages of Alzheimer’s disease.