Alzheimer disease (AD) is the leading cause of dementia, affecting more than 26 million people worldwide.1
Clinically, the disease is characterized by progressive memory loss and a decline in cognitive abilities. Several symptomatic treatments are in use for AD; however, no disease-modifying therapies are currently available. The two major pathological hallmarks of AD are extra cellular amyloid plaques, which are formed mainly from the amyloid-β (Aβ) peptide, and intracellular neurofibrillary tangles (NFTs), which contain hyperphosphorylated tau. Other pathological changes in the brain include gliosis, inflammation, neuritic dystrophy, neuron loss, and changes in neurotransmitter levels.2,3
In AD, the development of pathology in the brain is thought to precede cognitive symptoms and, hence, diagnosis of the disease, by many years.
The Aβ peptide, which comprises 40–42 amino acids, is generated following proteolytic cleavage of the amyloid precursor protein (APP).4
Several findings suggest that Aβ, particularly the 42 amino acid form (Aβ1–42
), is a major factor in the pathogenesis of AD. Mutations in APP
and in the genes that encode presenilins 1 and 2, (proteins involved in cleavage of APP) are associated with AD in a small number of families. Furthermore, Aβ is deposited in plaques and blood vessels in the brain early in the disease process. Finally, Aβ oligomers and fibrillar aggregates are toxic to neurons.5–7
The ‘amyloid cascade hypothesis’ (Box 1
) emphasizes a central role for Aβ in the pathogenesis of AD. Thus, Aβ has become a major therapeutic target, with various anti-Aβ strategies being pursued. These strategies include lowering the production of the peptide by inhibiting the enzymes responsible for Aβ generation, preventing the formation of Aβ aggregates, and increasing the rate of Aβ clearance from the brain. Aβ immunotherapy uses anti-Aβ antibodies, generated following vaccination or introduced passively, to increase the rate of clearance and prevent aggregation of this peptide ().
Box 1. The amyloid cascade hypothesis
The ‘amyloid cascade’ hypothesis places the formation of early, toxic amyloid-β(Aβ) oligomers and the accumulation of Aβ aggregates at the center of Alzheimer disease pathogenesis. This hypothesis states that over time, an imbalance in Aβ production and/or clearance leads to gradual accumulation and aggregation of the peptide in the brain, initiating a neurodegenerative cascade that involves amyloid deposition, inflammation, oxidative stress, and neuronal injury and loss.3,102,103
Supporting this hypothesis, in vitro
and in vivo
studies in animal models have shown that oligomeric and fibrillar forms of Aβ cause long-term potentiation impairment104,105
and synaptic dysfunction,106–108
and accelerate the formation of neurofibrillary tangles that eventually cause synaptic failure and neuronal death.109
Figure 1 Active and passive immunization approaches. a | Vaccination (active immunization) activates the body’s immune system to produce antigen-specific antibodies. In AD, full-length Aβ or a fragment of Aβ conjugated to a foreign T cell (more ...)
Over the past 10 years, Aβ immunotherapy has emerged from preclinical studies in transgenic mouse models of AD to enter clinical trials in humans. Presently, at least 13 different Aβ immunotherapies are in clinical trials worldwide.8
Adverse events, including meningo encephalitis and vasogenic edema, have been noted in some of these clinical trials. Nevertheless, studies of active and passive Aβ immunotherapies are continuing to move forward, with an estimated total enrollment of >9,000 patients. On the basis of results from preclinical and clinical studies, we believe that Aβ immunotherapy has strong potential for preventing AD if patients are immunized before disease onset or in the earliest stages of the disorder. In this Review, we will provide an overview of the preclinical studies in animal models that supported a role for Aβ immunotherapy in the prevention of AD pathogenesis and cognitive deficits. We also will summarize the details of the AN1792 vaccine trial and deliver an update on the active and passive Aβ immunotherapies currently in clinical trials. Lastly, we will outline what we perceive to be important considerations in the development of Aβ immunotherapy for preventing AD.