We describe events spanning over 20 years that have shaped our approach to identification of interventions that may delay symptoms in Alzheimer's disease (AD). These events motivated the development of a new Centre for Studies on Prevention of AD that includes an observational cohort of cognitively normal high-risk persons and INTREPAD, a nested two-year randomized placebo-controlled trial of the non-steroidal anti-inflammatory drug naproxen sodium. INTREPAD enrolled 217 persons and will follow 160 in a modified intent-to-treat analysis of persons who remained on-protocol through at least one follow-up evaluation. The trial employs dual endpoints: 1) a composite global cognitive score generated by a battery of 12 psychometric tests organized into five subscales; and 2) a summary Alzheimer's Progression Score derived from latent variable modeling of multiple biomarker data from several modalities. The dual endpoints will be analyzed by consideration of their joint probability under the null hypothesis of no treatment effect, after allowing appropriately for their lack of independence. We suggest that such an approach can be used economically to generate preliminary data regarding the efficacy of potential prevention strategies, thereby increasing the chances of finding one or more interventions that successfully prevent symptoms.
Keywords: Alzheimer’s disease; Prevention trials; biomarkers; pathogenesis.