%0 Journal Article %J J Alzheimers Dis %D 2018 %T Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer's Disease. %A Gabriel, António José %A Almeida, Maria Rosário %A Ribeiro, Maria Helena %A Carneiro, Diogo %A Valério, Daniela %A Pinheiro, Ana Cristina %A Pascoal, Rui %A Santana, Isabel %A Baldeiras, Ines %K Aged %K Alzheimer Disease %K Amyloid beta-Peptides %K Apolipoproteins E %K Biomarkers %K Butyrylcholinesterase %K Cognitive Dysfunction %K Disease Progression %K Female %K Genetic Predisposition to Disease %K Humans %K Kaplan-Meier Estimate %K Male %K Middle Aged %K Risk Factors %K tau Proteins %X

BACKGROUND: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K-variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited.

OBJECTIVE: To investigate the influence of the BuChE-K variant in MCI progression to AD.

METHODS: 96 MCI patients were included in the study and were genotyped for BuChE-K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels of AD biomarkers amyloid-β 42 (Aβ42), total and hyperphosphorylated tau (t-tau and p-tau) were also determined.

RESULTS: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Aβ42 were significantly lower and t-Tau, p-Tau, and ApoE ɛ4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE ɛ4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD.

CONCLUSION: 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.

%B J Alzheimers Dis %V 61 %P 1097-1105 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29254094?dopt=Abstract %R 10.3233/JAD-170695 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers. %A Ramos de Matos, Mafalda %A Ferreira, Catarina %A Herukka, Sanna-Kaisa %A Soininen, Hilkka %A Janeiro, André %A Santana, Isabel %A Baldeiras, Ines %A Almeida, Maria Rosário %A Lleo, Alberto %A Dols-Icardo, Oriol %A Alcolea, Daniel %A Benussi, Luisa %A Binetti, Giuliano %A Paterlini, Anna %A Ghidoni, Roberta %A Nacmias, Benedetta %A Meulenbroek, Olga %A van Waalwijk van Doorn, Linda J C %A Kuiperi, H Bea J %A Hausner, Lucrezia %A Waldemar, Gunhild %A Simonsen, Anja Hviid %A Tsolaki, Magda %A Gkatzima, Olymbia %A Resende de Oliveira, Catarina %A Verbeek, Marcel M %A Clarimón, Jordi %A Hiltunen, Mikko %A de Mendonça, Alexandre %A Martins, Madalena %X

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

%B J Alzheimers Dis %V 66 %P 639-652 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/30320580?dopt=Abstract %R 10.3233/JAD-180512 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Underlying Biological Processes in Mild Cognitive Impairment: Amyloidosis Versus Neurodegeneration. %A Santana, Isabel %A Baldeiras, Ines %A Santiago, Beatriz %A Duro, Diana %A Freitas, Sandra %A Pereira, Miguel Tábuas %A Almeida, Maria Rosário %A Oliveira, Catarina Resende %X

The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer's disease (AD), but this mandatory "amyloid-first pathway" has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42, and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1-18.0, p = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7-9.3, p = 0.141; SNAP: HR = 3.1, 95% CI = 1.1-9.6; p = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative "neurodegeneration-first pathway" for further investigation.

%B J Alzheimers Dis %V 64 %P S647-S657 %8 2018 %G eng %N s1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29562515?dopt=Abstract %R 10.3233/JAD-179908