The apolipoprotein E ε4 allele plays pathological roles in AD through high protein expression and interaction with butyrylcholinesterase

The apolipoprotein E (ApoE) epsilon 4 allele has consistently been established as an Alzheimer's disease (AD) risk factor, but its pathological contribution to AD is obscure. Certain butyrylcholinesterase (BuChE) polymorphisms together with the ApoE epsilon 4 allele synergistically increase the risk of AD. In addition, AD risk factors, i.e. advanced age, female gender and ApoE epsilon 4 are associated with different levels of CSF BuChE in AD patients, and BuChE protein attenuates A beta fibrillization in vitro. Here we investigated the roles of ApoE and BuChE gene products as modulators of pathological features of AD in vivo. We found that AD risk factors were associated with different levels of ApoE protein in the CSF of AD patients (n = 115). Women and ApoE epsilon 4 carriers had the highest levels of ApoE protein (up by 50-120%, p < 0.01-0.0001), which were increased with age (r = 0.30, p < 0.0006). The CSF surrogate markers of pathological features of AD, i.e. high tau and P-tau, low A beta(42) and high tau/A beta(42) ratio, were associated with high levels of ApoE protein. Intriguingly, high ApoE protein levels were not only associated with low amounts of BuChE, but they also altered the aging and activity of this enzyme in concentration-and isoform-dependent manners, particularly in the presence of A beta peptides. Both ApoE and BuChE levels were also differentially related to levels of the proinflammatory cytokine IL-1 beta. In conclusion, ApoE epsilon 4 might impart its pathological role through high protein expression and interaction with BuChE, which in turn might modulate central cholinergic activity and A beta load in the brain. (C) 2009 Elsevier Inc. All rights reserved.