Plasma acetylcholinesterase activity correlates with intracerebral β-amyloid load

Abstract

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.

Figure 1

Top row, patterns of PEB binding in Alzheimer’s disease (AD) compared to non-AD participants. Middle row, voxel-wise multi-linear regression of PIB binding and AChE activity, adjusting for age. sex, apolipoprotem E4 (ApoE4) allele status (carrier or non- carrier). Vascular Index and cholinesterase inhibitor (C’hE-I) treatment. Bottom row, voxel-wise multi-linear regression of PIB binding and BC’hE activity, adjusting for age. sex. apolipoprotem (ApoE4) allele status (carrier or non- carrier), excluding participants taking rivastigmine (a non-selective ChE-I that affects both AChE and BChE). All results are presented at a threshold of P < 0.001. uncorrected for multiple comparisons.

Figure 2

Partial regression plots show the relationships between PIB Index and Cholinesterase activity, (a) AChE vs PIB Index among all participants, with AChE-I symbols (b) AChE vs PIB Index among AD participants (c) AChE vs PIB Index among non AD participants (d) AChE vs PIB Index among participants naïve to AChE-I treatment (e) BChE vs PIB Index. Residuals are plotted for each participant to adjust for the effects of age, gender, Vascular Index, ApoE4 status and ChE-I treatment.

Figure 3

Activation of the cholinergic anti-inflammatory pathway - Microglial cells activated by Aβ plaques/ongoing systemic inflammation increase the secretion of proinflammatory cytokines. The cytokines activate the ‘cholinergic anti-inflammatory pathway’ which increases ACh release. As a response to increased ACh levels, AChE activity levels increase to dampen the effect.