4.3 Alzheimer's Disease
Background: The amyloid cascade hypothesis has been a major driving theory in Alzheimer’s disease (AD) research for decades. This hypothesis posits that amyloid-beta peptide build-up in the brain is a primary cause of, as well as a biomarker for, the neurodegeneration found in AD. Despite several failed drug development efforts targeting amyloid-beta, the amyloid cascade remains a dominant theoretical paradigm in AD research. But how many failures are required before the limited human and material resources for AD research ought to be directed elsewhere? Although AD is currently without any impressive disease-modifying therapies, the fact of unmet clinical need is not sufficient to justify an infinite consumption of resources and patient burden in the face of limited demonstrated benefit.
Aim: To map the research portfolio of amyloid-centric pharmaceuticals for Alzheimer’s disease, providing a comprehensive picture of the complete cost and benefit associated with the amyloid cascade hypothesis. We hypothesize that there will be considerable evidence of waste and poor uptake of evidence across the amyloid-centric AD research portfolio.
Approach: We will conduct a systematic literature search of Medline, Embase, and Clinicaltrials.gov for clinical trials of amyloid-beta targeting pharmaceuticals as a treatment for AD. The resulting reports and registration records will be extracted for demographics, clinical characteristics, study design properties, and outcome data. We will then perform a descriptive analysis of research and reporting activities, statistical meta-analysis of outcomes and data trends, and AERO graphing to chart the evolution of evidence for and against the amyloid-beta hypothesis, as well as the evidence supporting particular diagnostic methods for assaying a patient’s amyloid-beta accumulation and its correlation with disease progression.
A pilot search for this protocol identified 46 amyloid-centric agents and 154 registered trials of these agents on Clinicaltrials.gov.