Abstract
Alzheimer’s disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (Aβ) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics. Within the past decade convincing data has arisen positioning the soluble prefibrillar Aβ-aggregates as the prime toxic agents in AD. However, different Aβ aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Aβ is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function. Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Aβ-aggregates than to focus on a single aggregate species for immunization.
Highlights
Alzheimer’s disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population
Further investigations focused on the prefibrillar aggregates, the water-soluble oligomers, which are increased in AD-patients [9]
The oligomeric species show, so far, the best correlation to neuro-psychiatric analysis and synapse loss [12,13,14]. These results increased the impact of soluble, premature Aβ-aggregates in the disease progression of AD, which has been positioned in the reformulated amyloid cascade hypothesis by Selkoe and Walsh [15]
Summary
The reported and potentially relevant Aβaggregates range from the smallest possible aggregate – the dimer – up to particles with hundreds of kDa. It is conceivable that commonly used methods for Aβ characterization provide only an isolated view of individual Aβ-species as opposed to the entire spectrum of Aβaggregates. This has implications for immunization with Aβ-aggregates, since their fate after injection is entirely elusive owing to their transient nature. The selection of a geriatric-friendly application form might play an important role with respect to a “total compliance” It might be the more promising strategy to approach the whole spectrum of Aβ aggregates rather than to focus on a distinct aggregative species by acute treatment, to generally diminish Aβ by means of a control-released immunotherapy suitable for a geriatric population.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
