Regulation of attention and response to therapy in dementia by butyrylcholinesterase

Abstract

These findings indicate that the butyrylcholinesterase enzyme is a major regulator of attention especially in cholinergic deficiency states through its ability to hydrolyse acetylcholine. Pharmacologic manipulation of this enzyme may be a viable strategy in dementia treatment and, with butyrylcholinesterase genotyping, may provide pharmacogenomic treatment of dementia.

Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease

“…33 Moreover, in a predominantly dementia with Lewy bodies cohort, the BCHE-K variant is associated with enhanced attention at baseline and poorer response to rivastigmine treatment, compared with those who did not carry the K variant and had impaired attention at baseline. 32 Disease progression in those with the K variant was only 60% of that seen in the wild-type group. 32 Another study found that in severe AD, as defined by an MMSE p8, the rate of cognitive decline was lower in those subjects with the K variant.…”

“…32 Disease progression in those with the K variant was only 60% of that seen in the wild-type group. 32 Another study found that in severe AD, as defined by an MMSE p8, the rate of cognitive decline was lower in those subjects with the K variant. 46 This study found significantly better late cognitive response in BCHE-K carriers in moderate-to-severe disease (MMSE p15) ( Table 6).…”

“…31 Homozygous individuals have approximately 30% reduced plasma BuChE activity 31 and show a slower rate of cognitive decline. 32,33 Lehmann et al 34 published the initial report of an association of BCHE-K with increased risk of AD. Several groups, including our own, 35 independently replicated this association.…”

“…45 BCHE-K is associated with improved attention compared with the wild-type BCHE gene and with a slower rate of cognitive decline. 32 BCHE-K has also been found to correlate with a slower rate of cognitive decline in severe AD (Mini-Mental State Examination (MMSE) p8) than the wild-type gene, but not at less severe stages of the disease. 46 The BCHE genotype has also been evaluated as a predictor of response to ChEI therapy.…”

Tetrahydrofurobenzofuran cymserine, a potent butyrylcholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis

“…The BuChE-K variant (Ala539Thr) is present in some 33% of Caucasian and Asian individuals, and those possessing two alleles for BuChE-K (homozygous) show an approximate 30% reduced BuChE activity (Bartels et al 1992;Ballard et al 2005). In an increasing number of studies where AD subjects were genotyped for BuChE genetic variants and their disease progression measured (O'Brien et al 2003;Holmes et al 2005;Ballard et al 2005;Déniz-Naranjo et al 2007), those with BuChE deficiency had a delayed onset of AD and a slower cognitive decline compared to patients with wild-type BuChE levels. The choice of which cymserine analogue to finally translate to clinical assessment will ultimately depend on the cost of bulk synthesis and tolerability in cellular and animal models.…”