4-[F-18]fluoro- N -{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N -(2-pyridinyl)benzamide, a selective serotonin 1A (5-HT _1A ) molecular imaging probe, was used in conjunction with positron emission tomography (PET) for quantification of 5-HT _1A receptor densities in the living brains of Alzheimer's disease patients (ADs) ( n = 8), subjects with mild cognitive impairment ( n = 6), and controls ( n = 5). ADs had receptor densities significantly decreased in both hippocampi (binding potential: controls 1.62 ± 0.07; ADs 1.18 ± 0.26) and also in raphe nuclei (controls 0.63 ± 0.09; ADs 0.37 ± 0.20). When volume losses are included, 5-HT _1A losses are even more severe (i.e., average mean decreases of 24% in mild cognitive impairment patients and 49% in ADs). A strong correlation of 5-HT _1A receptor decreases in hippocampus with worsening of clinical symptoms (Mini Mental State Exam scores) was also found. Moreover, these decreases in 5-HT _1A receptor measures correlate with decreased glucose utilization as measured with 2-deoxy-2-[F-18]fluoro- d -glucose PET in the brains of ADs (standardized uptake values; globally: controls 0.89 ± 0.04, ADs 0.72 ± 0.04; posterior cingulate gyrus: controls 1.05 ± 0.09, ADs 0.79 ± 0.11). They also inversely correlate with increased neuropathological loads measured with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile PET in several neocortical regions in the same subjects. The in vivo observations were confirmed independently by in vitro digital autoradiography with 4-[F-18]fluoro- N -{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}- N -(2-pyridinyl)benzamide and 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile on brain tissue specimens from two ADs and three nondemented subjects.