Background: Previous studies have demonstrated alterations in the peripheral cholinergic system in Alzheimer's disease (AD), though results have been inconsistent and not linked to in vivo biomarkers of pathology. We examined the relationship between amyloid-beta (Aβ) plaques and plasma cholinesterase activity in a heterogeneous dementia population. Methods: 29 participants with clinical AD and 35 with non-AD diagnoses underwent positron emission tomography (PET) with the amyloid ligand [11C] PIB and plasma measurements of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity. Multi-linear regression was used to evaluate the relationship between AChE or BChE activity and PIB binding (adjusted for age, sex, apolipoprotein E4 and vascular risk), applying voxel-wise and region of interest (ROI) approaches. AChE activity was further adjusted for cholinesterase inhibitor (ChE-I) use. Global amyloid load was measured using a PIB Index, representing mean tracer binding in frontal, parietal, lateral temporal and cingulate cortex. Results: AChE activity was correlated with PIB Index (β=0.39, p<0.001) and with regional PIB binding in frontal, temporal, parietal and occipital lobes, precuneus and posterior cingulate on both voxel-wise (p<0.001 uncorrected) and ROI (β=0.26-0.41, p<0.005) analysis. Correlations remained significant after covarying clinical diagnosis (β=0.42, p=0.001), and among participants naive to ChE-I (β=0.51, p=0.005). No correlation was found between BChE activity and PIB. Among AD participants, disease severity was not correlated with AChE, BChE or PIB Index. Conclusion: AChE activity in plasma is correlated with brain Aβ load. Activation of the 'anti-inflammatory cholinergic pathway' may provide the link between Aβ plaques and peripheral cholinergic measures.