Abstract
There are nearly 50 million people with Alzheimer's disease (AD) worldwide and currently no disease modifying treatment is available. AD is characterized by deposits of Amyloid-β (Aβ), neurofibrillary tangles, and neuroinflammation, and several drug discovery programmes studies have focussed on Aβ as therapeutic target. Active immunization and passive immunization against Aβ leads to the clearance of deposits in humans and transgenic mice expressing human Aβ but have failed to improve memory loss. This review will discuss the possible explanations for the lack of efficacy of Aβ immunotherapy, including the role of a pro-inflammatory response and subsequent vascular side effects, the binding site of therapeutic antibodies and the timing of the treatment. We further discuss how antibodies can be engineered for improved efficacy.
Highlights
Alzheimer’s Disease (AD) is the most common cause of dementia worldwide, characterized by variable mood changes, difficulty carrying out daily tasks, confusion, and progressive memory loss
Asymptomatic and resolvable ARIA-E was observed after the first or second infusion of AAB-003, but the dose at which ARIA-E was observed was considerably higher compared to Bapineuzumab (1 mg/kg), a finding that supports the hypothesis that reducing Fc-receptor effector function may reduce the risk of ARIA associated with monoclonal antibodies targeting aggregated cerebral amyloid
The results showed that 3D6 is effective in preventing amyloid deposition in 9 month old PDAPP mice, while in 18–21 month aged PDAPP mice it fail to show any effect on amyloid load and showed an exacerbation of cerebral amyloid angiopathy (CAA)-related microhemorrhage
Summary
Alzheimer’s Disease (AD) is the most common cause of dementia worldwide, characterized by variable mood changes, difficulty carrying out daily tasks, confusion, and progressive memory loss. Additional risk factors for AD which are beyond the scope of this review, include diabetes, high blood pressure, obesity, smoking, depression, as well as physical, and cognitive inactivity Most of these are modifiable which gives hope to effort to reduce the incidences of AD. There is increasing evidence that poor sleep leads to higher levels of Aβ in the brain, and in turn aberrant Aβ levels further interferes with sleep and by extension memory consolidation (Diekelmann et al, 2009; Carvalho et al, 2018). This would suggest that targeting sleep represents a future avenue for treating AD. In this review we will describe the past, present and future directions of amyloid beta targeting immunotherapy and its potential as a disease modifying therapy for AD
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