Butyrylcholinesterase genotype and gender influence Alzheimer's disease phenotype

Abstract

Retrospective data are presented to support a spectrum of early Alzheimer's disease (AD) along a continuum defined by gender and genotype. The putative neurodegenerative mechanisms driving distinct phenotypes at each end of the spectrum are glial hypoactivity associated with early failure of synaptic cholinergic neurotransmission and glial overactivation associated with loss of neural network connectivity due to accelerated age-related breakdown of myelin. In early AD, male butyrylcholinesterase K-variant carriers with one or two apolipoprotein ɛ4 alleles have prominent medial temporal atrophy, synaptic failure, cognitive decline, and accumulation of aggregated beta-amyloid peptide. Increasing synaptic acetylcholine in damaged but still functional cholinergic synapses improves cognitive symptoms, whereas increasing the ability of glia to support synapses and to clear beta-amyloid peptide might be disease-modifying. Conversely, chronic glial overactivation can also drive degenerative processes and in butyrylcholinesterase K-variant negative females generalized glial overactivation may be the main driver from mild cognitive impairment to AD. Females are more likely than males to have accelerated age-related myelin breakdown, more widespread white matter loss, loss of neural network connectivity, whole brain atrophy, and functional decline. Increasing extracellular acetylcholine levels blocks glial activation, reduces myelin loss and damage to neural network connectivity, and is disease-modifying. Between extremes characterized by gender, genotype, and age, pathophysiology may be mixed and this spectrum may explain much of the heterogeneity of amnestic mild cognitive impairment. Preservation of the functional integrity of the neural network may be an important component of strengthening cognitive reserve and significantly delaying the onset and progression of dementia, particularly in females. Prospective confirmation of these hypotheses is required. Implications for future research and therapeutic opportunities are discussed.

Effect of Rivastigmine or Memantine Add-on Therapy Is Affected by Butyrylcholinesterase Genotype in Patients with Probable Alzheimer's Disease

“…Or the difference according to the presence of BCHE-K is not prominent enough to be detected by MMSE or other clinical outcomes. In a previous report, the female gender may have been beneficial in the presence of BCHE-K , but interaction between BCHE-K and gender was not observed in the present study [5]. However, since more than three-fourths of patients were women in this study, gender effect might be difficult to be detected in this proportion.…”

“…The K variant of the BCHE gene (BCHE-K) , which is the most common single-nucleotide polymorphism of BCHE on chromosome 3q26 (Ala 539 Thr), inherently exhibits 30% reduced BCHE activity [2]. Although there are some controversies, the presence of the BCHE-K allele is believed to reduce the risk of AD in apolipoprotein E ε 4 (APOE4) non-carriers and delay the onset and progression of AD [3,4,5,6]. …”

Impact of Functional Deficits in Instrumental Activities of Daily Living in Mild Cognitive Impairment

“…13, 14 In this study, after adjusting for standard tests of episodic verbal memory, attention/processing speed and task switching/executive test performance, informant-reported functional deficits still strongly predicted the progression to dementia. Biomarkers such as olfactory identification deficits, 5 MRI medial temporal and posterior cortical atrophy, 18 PET indices of metabolism and amyloid load, 19 and cerebrospinal fluid Abeta, tau and phospho tau 20 levels show predictive utility for the progression from MCI to AD, 21 but their added predictive value over and above clinical, functional and cognitive assessment is not fully established. Assessment of neuroimaging and cerebrospinal fluid biomarkers can be expensive and time-consuming.…”

Memory-enhancing and brain protein expression-stimulating effects of novel calcium antagonist in Alzheimer’s disease transgenic female mice

“…Females also show an exacerbated effect of ApoE genotype [30–32], the factor which putatively can impair memory. Moreover, females are more likely than males to have accelerated age-related myelin breakdown, white matter loss and hence, damage of neural network connectivity [33, 34]. Gender-specific AD therapy [35] is not common, only some studies demonstrated beneficial effects of anticholinesterase drug rivastigmine in the female subpopulation compared to men [36, 37].…”