Hunting for an Antigen: Humoral Immunity in Alzheimer's Disease

Alzheimer's disease (AD) is the leading cause of dementia, affecting millions of individuals on a global scale. A fatal and incurable neurodegenerative disease, AD is defined by various molecular and cellular abnormalities, such as the formation of intracellular neurofibrillary tangles and extracellular amyloid plaque deposition, leading to increased neuroinflammation, parenchymal tissue breakdown, and cognitive deficiencies. These pathological conditions are associated with the disruption of the blood-brain barrier (BBB), which is the protective network of cells responsible for maintaining homeostasis at the borders of the central nervous system (CNS). The breakdown of the BBB results in a dysregulation of the neuroimmune axis. The induction of inflammatory and autoimmune responses has been a key topic of study in AD, particularly surrounding innate immune cell activation. Recent discoveries focusing on the adaptive immune branch in the diseased CNS show evidence of effector and memory T cell activation and expansion, highlighting the complex relationship of the neuroimmune axis. It is speculated that humoral immunity might play a significant role in pathology through the production of autoantibodies. However, the contribution of B cells and plasma cells is unclear. We aim to review the literature addressing the following questions: are B cells protective or pathogenic in the CNS during AD, and do their antibodies have specific antigenic targets within this niche? The characterization of humoral contributions to immune dysregulation in AD is critical to the development of novel therapeutic strategies to slow or prevent neurodegeneration and cognitive impairment.