Critical Issues for Successful Immunotherapy in Alzheimer's Disease: Development of Biomarkers and Methods for Early Detection and Intervention
Authors: Tarawneh, Rawan; Holtzman, David M.
Source: CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders), Volume 8, Number 2, April 2009 , pp. 144-159(16)
Publisher: Bentham Science Publishers
Abstract:Over the last 10 years, promising data has emerged from both animal and human studies that both active immunization with amyloid-β (Aβ) as well as passive immunization with anti-Aβ antibodies offer promise as therapies for Alzheimer's disease (AD). Data from animal models suggests that antibodies to Aβ through several mechanisms can decrease Aβ deposition, decrease Aβ -associated damage such as dystrophic neurite formation, and improve behavioral performance. Data from human studies suggests that active immunization can result in plaque clearance and that passive immunotherapy might result in slowing of cognitive decline. Despite this, a recent analysis from a phase I trial that involved active immunization with Aβ42, while not powered to determine efficacy, suggested no large effect of active immunization despite the fact that plaque clearance was very prominent in some subjects. An important issue to consider is when active or passive immunization targeting Aβ has the chance to be most effective. Clinico-pathological and biomarker studies have shown that in terms of the time course of AD, Aβ deposition probably begins about 10-15 years prior to symptom onset (preclinical AD) and that tau aggregation in tangles and in neurites does not begin to accelerate and build up in larger amounts in the neocortex until just prior to symptom onset. By the time the earliest clinical signs of AD emerge, Aβ deposition may be close to reaching its peak and tangle formation and neuronal cell loss is substantial though still not at its maximal extent. Since immunization targeting Aβ does not appear to have major effects on tangle pathology, for immunization to have the most chance for success, performing clinical trials in individuals who are cognitively only very mildly impaired or even in those with preclinical AD would likely offer a much better chance for success. Current work with AD biomarkers suggests that such individuals can now be identified and it seems likely that targeting this population with immunization strategies targeting Aβ would offer the best chance of success.
Document Type: Research Article
Publication date: April 1, 2009
- CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.