A review of immunotherapies targeting the accumulation of amyloid-beta. A cure for Alzheimer’s disease?

School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, England, BS8 1TD, UK

Alzheimer’s disease (AD) is the most prevalent form of dementia in the world. It is characterised by widespread neurodegeneration in the cerebral cortex and limbic system, which leads to the progressive deterioration of memory and cognitive functions. The accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau protein produces the two primary neuropathological hallmarks of AD: amyloid plaques and neurofibrillary tangles (NFTs). Both genetic and experimental evidence supports the role of Aβ in instigating AD and being an upstream regulator of hyperphosphorylated tau, making it a desirable target for novel disease-modifying therapeutics. Active and passive immunisation targeting Aβ in murine models of AD have provided promising therapeutic results. However, both immunisation strategies have failed to reduce cognitive decline in mild to moderate AD patients in late clinical trials. Limited antibody exposure to the brain and therapeutic treatment implemented too late in AD progression could account for a lack of clinical efficacy. Therefore, preventative passive immunotherapy trials are currently investigating whether earlier treatment intervention in the preliminary stages of AD can slow or prevent disease progression. Furthermore, hybrid antibodies that capitalise on the use of endogenous transport systems to improve antibody concentration and penetration in the cerebral parenchyma could provide a much-needed solution to the problem of limited brain exposure. This review aims to explain the advances, failures and the potential future of Aβ immunotherapies, with particular emphasis on our current understanding of the pathological mechanisms of the amyloid pathway.

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