Effects of pioglitazone on mnemonic hippocampal function: A blood oxygen level–dependent functional magnetic resonance imaging study in elderly adults

INTRODUCTION: Mitochondrial dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). Accordingly, drugs that positively influence mitochondrial function are being evaluated in delay-of-onset clinical trials with at-risk individuals. Such ongoing clinical research can be advanced by developing a better understanding of how these drugs affect intermediate brain phenotypes associated with both AD risk and pathophysiology. METHODS: Using a randomized, parallel-group, placebo-controlled design in 55 healthy elderly volunteers, we explored the effects of oral, low-dose pioglitazone, a thiazolidinedione with promitochondrial effects, on hippocampal activity measured with functional magnetic resonance imaging during the encoding of novel face–name pairs. RESULTS: Compared with placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg, or 6.0 mg) administered daily for 14 days was associated with significant increases in right hippocampal activation during encoding of novel face–name pairs at day 7 and day 14, relative to baseline. DISCUSSION: Our exploratory analyses suggest that low-dose pioglitazone has measurable effects on mnemonic brain function associated with AD risk and pathophysiology.