Commentary on “Challenges to demonstrating disease-modifying effects in Alzheimer’s disease clinical trials”

Abstract

The distinction between disease-modifying effects and symptomatic benefits in Alzheimer’s disease (AD) therapeutic research carries significance for clinicians, patients and families, and the pharmaceutical industry. Complex trial designs have been proposed to allow definitive distinction, but these carry substantial methodologic difficulties. Utilization of biomarkers of disease state as secondary outcome measures may provide some evidence in support of a treatment effect on pathophysiology. However, if a therapeutic agent lacks any short-term symptomatic benefit but shows a conclusive effect on the rate of decline with longterm treatment, analysis of the primary cognitive and clinical data from a simple parallel group trial may be sufficient to indicate disease modification. The focus of most academic and pharmaceutical industry therapeutic research on AD is the development of interventions that will favorably alter the underlying pathophysiology. Dr. Jeffrey Cummings’ excellent and illuminating discussion of disease modification trial design issues [1] reviews the challenges that face investigators in the field. Cummings’ definition of a disease-modifying treatment as “a pharmacologic treatment that retards the underlying process of AD by intervening in the neurobiological processes that constitute the pathology and pathophysiology of the disease and lead to cell death or dysfunction” is reasonable, reflecting regulatory and research views. His discussion of the drug development process is based on the amyloid hypothesis, which, on the basis of very broad and strong evidence, is justifiably accepted by most investigators. But perhaps there is still room for a broader perspective. The minority view that questions the pivotal role of increased amyloid peptide generation has recently gained some strength. The most powerful argument in favor of the amyloid hypothesis has been that it is the only reasonable explanation for the observation that all genetic causes of AD, including the mutations of the amyloid precursor protein and presenilins 1 and 2 (now known to be components of the gamma secretase complex) directly increase generation of the amyloid peptide. But it has now been shown that some presenilins 1 mutations cause AD without increasing gamma secretase cleavage of the amyloid precursor protein [2], suggesting a more complex pivotal mechanism. Those seeking disease-modifying therapies may be advised to remain open to alternative hypotheses and drug targets. In practice, the distinction between disease modification