Antibody Therapy for Alzheimer’s Disease – Key Challenges
Alzheimer’s disease (AD) is characterized by the deposition of toxic protein aggregates in the brain, e.g. beta-amyloid peptides and tau proteins. Lowering such protein aggregates constitutes a major target for treatment and prevention of AD and related conditions. Enrolling subjects based on clinical criteria alone, however, may result in misclassification as evidenced by the relatively high percent of subjects negative on PET beta-amyloid scans in subgroups of two completed phase 3 studies. Consequently, novel study protocols were designed testing immunotherapy in subjects with proven beta-amyloid deposition in brain (Sevigny et al., Nature 2016). In addition, novel study protocols selected patients in earlier, even prodromal stages, e.g. PET beta-amyloid positive subjects with mild cognitive impairment (MCI) due to AD. Key challenges of immunotherapy include targeting the most relevant Aβ species, establishing a consistent dose-response, selecting the right timing and duration of the intervention, demonstrating a clinical / biomarker correlation and managing amyloid related imaging abnormalities (ARIA E/H). Novel imaging modalities using PET ligands allowing the assessment of amyloid and tau deposits along with advanced MRI measurements may help to identify the most suitable study population and to select appropriate biomarker and clinical endpoints for the monitoring of long-term outcome.
Christoph Hock, M.D. -
Professor and Director, Institute for Regenerative Medicine,
University of Zurich