Immune attack: the role of inflammation in Alzheimer disease

Key Points Alzheimer disease (AD), like other proteinopathic neurodegenerative disorders, is characterized by the accumulation of amyloidogenic proteins A neuroinflammatory component in AD has been known for more than a decade; however, the importance of the contribution of inflammation in the pathogenesis of AD has been appreciated only recently. Genetic and bioinformatic data from individuals with AD and insights from preclinical models now substantiate the present view that inflammation participates in and exacerbates AD pathology. Neuroinflammation in AD is primarily driven by the brain's intrinsic myeloid cells (known as microglia) and escalates with disease progression; thus AD-associated neuroinflammation contrasts with traditionally defined neuroinflammatory diseases such as multiple sclerosis and encephalitides, which are mainly driven by blood-derived leukocytes and B and T lymphocytes, invading the CNS. Manipulation of some of the molecules of the innate immune system or their respective pathways in animal models of AD has resulted in substantial alteration of disease pathology, indicating the potential to ameliorate the disease course through targeting components of the immune system. The immune system thus appears to provide exciting novel and accessible targets for the diagnosis, control and treatment of AD; however, precise knowledge about specific and defined immune events, which may change during the disease course or differ among individuals with AD, is required. Diagnostics research needs to develop sensitive methods to detect immune alterations prior to the onset of AD to identify those patients at risk who may benefit most from specific, tailored anti-inflammatory interventions. It is now emerging that the neuroinflammation that is associated with Alzheimer disease may have a key role in driving this disease. In this Review, Heppner, Ransohoff and Becher examine the contribution of the immune system to the pathogenesis of this disorder. The past two decades of research into the pathogenesis of Alzheimer disease (AD) have been driven largely by the amyloid hypothesis; the neuroinflammation that is associated with AD has been assumed to be merely a response to pathophysiological events. However, new data from preclinical and clinical studies have established that immune system-mediated actions in fact contribute to and drive AD pathogenesis. These insights have suggested both novel and well-defined potential therapeutic targets for AD, i