OBJECTIVE: Recent studies have suggested modifications of serotonin cerebral metabolism and of 5-HT(1A) receptors density in Alzheimer disease (AD). This study aims at exploring hippocampus 5-HT(1A) receptor density in patients at the amnesic mild cognitive impairment (aMCI) and mild AD dementia stages. METHODS: With use of PET with a selective 5-HT(1A) antagonist, 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine ([(18)F]MPPF), the hippocampus 5-HT(1A) binding potential (BP) was quantified in 10 patients with mild AD, in 11 patients with aMCI, and in 21 aged paired control subjects. To take into account hippocampal atrophy, a partial volume correction was applied to the [(18)F]MPPF data, leading to the calculation of a corrected BP (BP(c)). Comparison of hippocampus BP over populations was performed using Kruskal-Wallis rank analysis. RESULTS: Hippocampus serotonergic receptor binding distinguishes patients from controls and patients with aMCI from patients with AD. In aMCI patients, the mean hippocampus BP(c) was 59% higher than the controls' (p < 0.005), and it was conversely 35% lower in patients with mild AD (p < 0.01). The difference in BP(c) values between patients with aMCI and mild AD was large, resulting in a p value of <0.0005. These differences were not related to hippocampus atrophy. CONCLUSION: A compensatory mechanism illustrated by an up-regulation of serotonergic metabolism has been shown at the stage of amnesic mild cognitive impairment (aMCI) in contrast with a dramatic decrease at later stages of Alzheimer disease (AD). This difference of hippocampus serotonergic receptor labeling allows distinguishing of patients with aMCI from those with mild AD. Exploring 5-HT(1A) receptors with 2'-methoxyphenyl-(N-2'-pyridinyl)-p-(18)F-fluoro-benzamidoethylpiperazine PET seems to be of interest for better understanding pathophysiologic changes at early stages of AD.