Positron emission tomography (PET) studies have demonstrated reduced acetylcholine esterase (AChE) activity as an indicator of cholinergic impairment, which is a main pathogenic process in Alzheimer's disease (AD). The E4 allele of apolipoprotein epsilon (ApoE4) is a major risk factor for AD. We examined the relation between ApoE-genotype and cortical AChE activity. In 19 patients (mean age 64) with mild to moderate AD (mean MMSE 22) PET with C-11-labeled N-methyl-4-piperidyl-acetate (MP4A) was performed and the ApoE4-genotype was determined. Parametric images of AChE hydrolysis were generated using a non-invasive technique and analysed globally and regionally. A neuropsychological battery testing memory, attention, executive functions, visuoconstruction, and language was administered. The mean cortical AChE activity was reduced significantly in both groups compared to reference values. The ApoE4 positive subjects (two homozygotes, nine heterozygotes) had significantly higher (p<0.05) AChE levels (MP4A hydrolysis rate 0.0753+/-0.0088min(-1)) than the ApoE4 negative subjects (n=8, 0.0654+/-0.0090min(-1)). Both groups were comparable with regard to age (63 versus 65) and dementia severity (MMSE 20 versus MMSE 22). AChE-impairment correlated significantly with the word fluency task (r=0.041, p<0.05) in the ApoE4 negative group only. These results indicate that cortical AChE activity is relatively well preserved in ApoE4 carriers, either by preservation of its cellular expression or as AChE activity in amyloid plaques.