Emerging hypotheses regarding the influences of butyrylcholinesterase-K variant, APOE epsilon 4, and hyperhomocysteinemia in neurodegenerative dementias.

Non-enzymatic functions of butyrylcholinesterase (BuChE) include prevention of the aggregation of amyloid-beta peptide (A beta) in a concentration-dependent manner. This is mediated by the C-terminus of the protein, distal from the enzymatic site. The BuChE-K variant polymorphism lowers expression of BuChE protein and/or alters C-terminal activity. In combination with factors that increase production or reduce elimination of A beta, and/or increase susceptibility to A beta toxicity - such as the apolipoprotein E (APOE) epsilon 4 allele and/or hyperhomocysteinemia - BuChE-K may accelerate cholinergic synaptic and neuronal damage and cognitive decline. A beta-mediated damage to ascending cholinergic pathways may be further accentuated by Lewy body and/or cerebrovascular disease. As the disease advances and functioning cholinergic synapses disappear, both the rapid cognitive decline and response to cholinesterase inhibitor therapy in individuals with these factors may diminish. Non-enzymatic functions of the BuChE protein, APOE epsilon 4 status and hyperhomocysteinemia influence the progression of pathology, symptom expression, and response to cholinesterase inhibition in a stage-specific manner in neurodegenerative disorders associated with Alzheimer, Lewy body and vascular pathology.