Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer’s Disease

Gabriel, António; Almeida, Maria Rosário; Ribeiro, Maria Helena; Carneiro, Diogo Reis; Valério, Daniela; Pinheiro, Ana Cristina; Pascoal, Rui; Santana, Isabel; Baldeiras, Inês

doi:10.3233/jad-170695

Cited by 9 publications

(5 citation statements)

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“…Butyrylcholinesterase (BChE) is an enzyme which splits choline compounds as well as other esters 19. For a long time BChE was thought to have a less important function, but recent literature demonstrated that BChE may in part and with a significantly slower rate and affinity act as a substitute in the absence of AChE with a relevant role in the development of a cholinergic deficit 20 21…”

Section: Introductionmentioning

confidence: 99%

Cholinesterase alterations in delirium after cardiosurgery: a German monocentric prospective study

et al. 2020

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ObjectivesPostoperative delirium (POD) is a common complication after elective cardiac surgery. Recent evidence indicates that a disruption in the normal activity of the cholinergic system may be associated with delirium.DesignProspective observational study.SettingSingle-centre at a European academic hospital.Primary and secondary outcome measuresIn our study the enzyme activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined preoperatively as well as on the first and second postoperative day. The confusion assessment method for the intensive care unit was used to screen patients for the presence of POD.ResultsA total of 114 patients were included in the study. POD was associated with a decrease in BChE activity on postoperative day 1 (p=0.03). In addition, patients who developed POD, had significantly lower preoperative AChE activity than patients without POD (p<0.01). Multivariate analysis identified a preoperatively decreased AChE activity (OR 3.1; 95% CI 1.14 to 8.46), anticholinergic treatment (OR 5.09; 95% CI 1.51 to 17.23), elevated European System for Cardiac Operative Risk Evaluation (OR 3.68; 95% CI 1.04 to 12.99) and age (OR 3.02; 95% CI 1.06 to 8.62) to be independently associated with the development of POD.ConclusionsWe conclude that a reduction in the acetylcholine hydrolysing enzyme activity in patients undergoing cardiac surgery may correlate with the development of POD.

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Section: Introductionmentioning

confidence: 99%

Cholinesterase alterations in delirium after cardiosurgery: a German monocentric prospective study

et al. 2020

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“…In APOE4 carriers, reduced BuChE activity is more marked in BCHE-K carriers, with a BCHE-K allele dose-dependent reduction in BuChE activity and lowering of glial activation markers (24, 29). The BCHE-K and APOE4 alleles significantly interact to reduce the age-at-onset of AD (30), and to increase the likelihood of progression from mild cognitive impairment (MCI) to AD (27, 31) and from cognitively unimpaired older individuals to early AD (26). Carriers of both APOE4 and BCHE-K alleles in the MCI stage of AD have a limbic-amnestic phenotype and progress most rapidly in the mild stage of AD, where they are the only genotype group with a significant response to AChE-I treatment (27, 31–33).…”

Section: Introductionmentioning

confidence: 99%

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

Lane,

Darreh-Shori,

Junge

et al. 2024

Preprint

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BackgroundWe wished to examine the impact of the K-variant ofbutyrylcholinesterase(BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) inAPOE4carriers.MethodsIn 45 patients, aged 50-74 years, with cerebrospinal fluid (CSF) biomarker confirmed mild AD, recruited into a clinical trial (NCT03186989), baseline demographics, disease characteristics, and biomarkers were evaluated byBCHE-KandAPOE4allelic status.ResultsInAPOE4carriers (N = 33), mean age-at-diagnosis of AD inBCHE-Kcarriers (n = 11) was 6.4 years earlier than inBCHE-Knoncarriers (n = 22,P <.001, ANOVA). InAPOE4noncarriers (N = 12) there was no similar influence ofBCHE-K. InAPOE4carriers with versus those withoutBCHE-K, mean age-at-baseline was over 6 years earlier and accompanied by slightly higher amyloid and tau accumulations. A predominant amyloid, limited tau pathophysiology, and limbic-amnestic phenotype was exemplified byAPOE4homozygotes withBCHE-K. Multiple regression analyses demonstrated association of amyloid accumulation withAPOE4carrier status (P <.029), larger total brain ventricle volume (P <.021), less synaptic injury (Ng,P <.001), and less tau (p-tau181,P <.005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL,P= .002), more synaptic injury (Ng,P <.001), and higher levels of glial activation (YKL-40,P= .01).ConclusionFindings concern the genetic architecture of prognosis in early AD, that is fundamental for patients and the design of clinical trials, and that is less well established than the genetics of susceptibility. In mild AD patients aged less than 75 years, the mean age-at-diagnosis of AD inAPOE4carriers was reduced by over 6 years inBCHE-Kcarriers versus noncarriers. Functional activation of glia may explain much of the effects ofAPOE4andBCHE-Kon the phenotype of early AD.

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“…In APOE4 carriers, reduced BuChE activity is more marked in BCHE-K carriers, with a BCHE-K allele dose-dependent reduction in BuChE activity and lowering of glial activation markers [ 24 , 29 ]. The BCHE-K and APOE4 alleles interact to significantly reduce the age-at-onset of AD [ 30 ], and to increase the likelihood of progression from mild cognitive impairment (MCI) to AD [ 27 , 31 ] and from cognitively unimpaired older individuals to early AD [ 26 ]. Carriers of both APOE4 and BCHE-K alleles in the MCI stage of AD have a limbic-amnestic phenotype and progress most rapidly in the mild stage of AD, where they are the only genotype group with a significant response to AChE-I treatment [ 27 , 31 – 33 ].…”

Section: Introductionmentioning

confidence: 99%

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

Lane,

Darreh-Shori,

Junge

et al. 2024

BMC Neurol

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Background The authors sought to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers. Methods Patients aged 50–74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study. Results In APOE4 carriers (N = 33), the mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P < .001, ANOVA). In APOE4 noncarriers (N = 12) there was no observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an association of amyloid accumulation with APOE4 carrier status (P < .029), larger total brain ventricle volume (P < .021), less synaptic injury (Ng, P < .001), and less tau pathophysiology (p-tau181, P < .005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL, P = .002), more synaptic injury (Ng, P < .001), and higher levels of glial activation (YKL-40, P = .01). Conclusion These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD aged less than 75 years, the mean age-at-diagnosis of AD in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype. Trial registration NCT03186989 since June 14, 2017

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Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer’s Disease

Abstract: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE ɛ4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients.

Cited by 9 publications

References 39 publications

Cholinesterase alterations in delirium after cardiosurgery: a German monocentric prospective study

Cholinesterase alterations in delirium after cardiosurgery: a German monocentric prospective study

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

Onset of Alzheimer disease in apolipoprotein ɛ4 carriers is earlier in butyrylcholinesterase K variant carriers

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