There are several mechanisms which might explain the effect of BCHE on Aβ plaque burden. Genetic variation at BCHE has been associated with increased cortical butyrylcholinesterase activity in autopsy tissue from elderly individuals with dementia.31 Increased enzyme activity, leading to decreased acetylcholine levels, may disrupt synaptic functioning, glial cell activation, and myelin maintenance to favor Aβ plaque formation and neurodegeneration.32 Indeed, cholinesterase inhibitors are presently first-line symptomatic therapies for AD,33 and drugs such as rivastigmine which inhibit butyrylcholinesterase are suggested to have potential disease-modifying effects in certain individuals compared to exclusive acetylcholinesterase inhibitors.34 Alternatively, through non-enzymatic functions butyrylcholinesterase may promote Aβ fibrillogenesis from soluble precursors35 or may interact with Aβ and ApoE to alter the cerebrospinal fluid environment36, 37 and to render developing plaques more resistant to clearance.38 Interestingly, butyrylcholinesterase activity has been associated with insulin resistance,39 and rs509208 in particular has been associated in a separate GWAS with diabetes-related traits,40 suggesting a broader role of the BCHE locus in disorders characterized by amyloidogenic protein accumulation.
