The proposed placebo-controlled clinical trial will test the hypothesis that rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist with insulin-sensitizing and anti-inflammatory properties, improves memory in persons with amnestic mild cognitive impairment (MCI). One hundred participants will be randomly assigned to receive 18 months of treatment with rosiglitazone or placebo, with cognitive assessment at 6 month intervals. They will also undergo serial structural magnetic resonance imaging (MRI) prior to and at the end of treatment to determine whether rosiglitazone ameliorates the rate of atrophy in medial temporal lobe (MTL) structures supporting memory. A subset of participants will receive lumbar punctures before and following treatment to determine whether rosiglitazone affects cerebrospinal fluid (CSF) levels of biomarkers associated with AD. This trial will provide valuable data regarding the effects of improved insulin sensitivity, reduced peripheral insulin levels, and reduced inflammation on cognitive function and biological markers in amnestic MCI, a likely prodromal phase of Alzheimer's disease (AD). Most importantly, this trial will elucidate the feasibility and potential efficacy of a novel treatment that may prevent or postpone the onset of AD. In doing so, we will lay the groundwork for future full-scale clinical trials of PPAR-gamma, agonists.
