摘要：

Background The rising numbers of people at risk for development of Alzheimer's disease (AD), and a greater understanding of the disease process, have focused attention on preventing or delaying the onset of AD symptoms. Objective: Design and conduct a double-blind, randomized, placebo-controlled, delay of onset trial to simultaneously (1) qualify a biomarker risk algorithm (biomarker) for predicting 5-year risk for developing mild cognitive impairment (MCI) due to AD, and (2) evaluate the efficacy of pioglitazone, a thiazolidinedione, as a treatment to delay the onset of MCI due to AD in cognitively normal elderly individuals. Methods Length variation of a poly T tract (rs-10524523) in the TOMM40 (translocase of outer mitochondrial membrane) gene is associated with age of onset of cognitive impairment or AD. TOMM40 is adjacent to, and in linkage disequilibrium with, the APOE gene. The biomarker incorporates an individual's current age along with TOMM40 and APOE genotypes. Several lines of evidence have suggested that thiazolidinediones may have utility in improving or preserving cognitive capability. Results A phase 3 clinical trial will evaluate the efficacy of pioglitazone to delay the onset of MCI due to AD. The design utilizes the biomarker for study enrichment by assigning subjects to high-risk groups (pioglitazone and placebo) for treatment evaluation and a low-risk placebo cohort to prospectively establish the positive and negative predictive values of the biomarker. The study will enroll approximately 5,000 participants and will operationalize the recently published clinical criteria (Alberts et al. 2011) for identifying subjects who develop MCI due to AD. It is designed as a time-to-event study and is anticipated to complete within 5 years. Conclusions The study is anticipated to begin enrolling participants in 4 Q 2012. Discussion with regulatory authorities in the US and EU are ongoing. This study provides an opportunity to explore therapeutic intervention in the presymptomatic phase of the AD continuum.

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