Current State of Immunotherapy for Alzheimer’s Disease

Abstract

There are currently over two dozen agents targeting β-amyloid (Aβ) in human clinical trials. More than a dozen of these are forms of anti-amyloid immunotherapy. Although other anti-amyloid interventions are further along in the development process, thus far only immunotherapy has provided post-mortem evidence that it can alter elements of the underlying pathology of Alzheimer’s disease (AD) in actual patients.In the past 30 years, there have been many attempts to develop treatments for AD. Early therapies were developed based on a limited understanding of the disease (Slide 1). Prior to the 1980s, a clear pathophysiologic mechanism for AD was not known; instead, symptomatic therapies targeted associated symptoms, such as agitation, insomnia, and psychosis. In the 1970s, several preclinical studies pointed toward synaptic transmission abnormalities, particularly neurochemical abnormalities, as the root cause of AD, and treatments with cholinesterase inhibitors grew out of that theory. Today, the cholinergic hypothesis has been largely discredited in the primary pathogenesis of AD. Another theory based on neurotransmitter abnormalities, the glutaminergic hypothesis, has also gone out of favor as a causal explanation for AD. This did not stop medications based on these mechanisms from finding a meaningful place in the clinical pharmacopeia for treatment of AD.In the 1990s, many clinical trials followed up on epidemiologic studies suggesting systemic causes of AD. These clinical trials focused on anti-inflammatories, hormone replacement, and antioxidants. The trials performed have largely failed, with the possible exception of the trials of vitamin E, an antioxidant. None of these agents have proven useful as disease-modifying therapies for symptomatic AD.