Kidins220 Correlates with Tau in Alzheimer’s Disease Brain and Cerebrospinal Fluid
Authors: Gamir-Morralla, Andrea | Belbin, Olivia | Fortea, Juan | Alcolea, Daniel | Ferrer, Isidro | Lleó, Alberto | Iglesias, Teresa
Article Type: Short Communication
Abstract: Identification of neurodegeneration-monitoring biomarkers would be of great clinical value for Alzheimer’s disease (AD) diagnosis. Using N- or C-terminal antibodies, we studied the pro-survival synaptic effector, Kidins220, in the brain and cerebrospinal fluid (CSF) of controls and AD patients. Only the N-terminal antibody showed a positive correlation between Kidins220 and phosphorylated tau in AD brains. Using this antibody, Kidins220 was detected in CSF from AD patients where it positively correlated with CSF phosphorylated tau and tau. This study highlights the potential of Kidins220 as a CSF biomarker in AD.
Keywords: Alzheimer’s disease, amyloid, antibody, ARMS, biomarkers, calpain, cerebrospinal fluid, excitotoxicity, Kidins220, tau protein
DOI: 10.3233/JAD-160639
Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1327-1333, 2017
Acetylcholinesterase Modulates Presenilin-1 Levels and γ-Secretase Activity
Authors: Campanari, Maria-Letizia | García-Ayllón, María-Salud | Belbin, Olivia | Galcerán, Joan | Lleó, Alberto | Sáez-Valero, Javier
Article Type: Research Article
Abstract: The cholinergic enzyme acetylcholinesterase (AChE) and the catalytic component of the γ-secretase complex, presenilin-1 (PS1), are known to interact. In this study, we investigate the consequences of AChE-PS1 interactions, particularly the influence of AChE in PS1 levels and γ-secretase activity. PS1 is able to co-immunoprecipitate all AChE variants (AChE-R and AChE-T) and molecular forms (tetramers and light subunits) present in the human brain. Overexpression of AChE-R or AChE-T, or their respective inactive mutants, all trigger an increase in PS1 protein levels. The AChE species capable of triggering the biggest increase in PS1 levels is a complex of AChE with the …membrane anchoring subunit proline-rich membrane anchor (PRiMA), which restricts the localization of the resulting AChE tetramer to the outer plasma membrane. Incubation of cultured cells with soluble AChE demonstrates that AChE is able to increase PS1 at both the protein and transcript levels. However, the increase of PS1 caused by soluble AChE is accompanied by a decrease in γ-secretase activity as shown by the reduction of the processing of the amyloid-β protein precursor. This inhibitory effect of AChE on γ-secretase activity was also demonstrated by directly assessing accumulation of CTF-AβPP in cell-free membrane preparations incubated with AChE. Our data suggest that AChE may function as an inhibitor of γ-secretase activity. Show more
Keywords: Acetylcholinesterase, Alzheimer's disease, γ-secretase, inhibitor, presenilin 1
DOI: 10.3233/JAD-140426
Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 911-924, 2014
Investigating Statistical Epistasis in Complex Disorders
Authors: Turton, James C. | Bullock, James | Medway, Christopher | Shi, Hui | Brown, Kristelle | Belbin, Olivia | Kalsheker, Noor | Carrasquillo, Minerva M. | Dickson, Dennis W. | Graff-Radford, Neill R. | Petersen, Ronald C. | Younkin, Steven G. | Morgan, Kevin
Article Type: Research Article
Abstract: The missing heritability exhibited by late-onset Alzheimer's disease is unexplained and has been partly attributed to epistatic interaction. Methods available to explore this are often based on logistic regression and allow for determination of deviation from an expected outcome as a result of statistical epistasis. Three such methodologies including Synergy Factor and the PLINK modules, –epistasis and –fast-epistasis, were applied to study an epistatic interaction between interleukin-6 and interleukin-10. The models analyzed consisted of two synergistic interactions (SF ≈ 4.2 and 1.6) and two antagonistic interactions (SF ≈ 0.9 and 0.6). As with any statistical test, power to detect association …is paramount; and most studies will be underpowered for the task. However, the availability of large sample sizes through genome-wide association studies make it feasible to examine approaches for determining epistatic interactions. This study documents the sample sizes needed to achieve a statistically significant outcome from each of the methods examined and discusses the limitations/advantages of the chosen approaches. Show more
Keywords: Complex disorders, epistasis, LOAD, modeling, PLINK, synergy factor
DOI: 10.3233/JAD-2011-110197
Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 635-644, 2011
The Epistasis Project: A Multi-Cohort Study of the Effects of BDNF, DBH, and SORT1 Epistasis on Alzheimer’s Disease Risk
Authors: Belbin, Olivia | Morgan, Kevin | Medway, Chris | Warden, Donald | Cortina-Borja, Mario | van Duijn, Cornelia M. | Adams, Hieab H.H. | Frank-Garcia, Ana | Brookes, Keeley | Sánchez-Juan, Pascual | Alvarez, Victoria | Heun, Reinhard | Kölsch, Heike | Coto, Eliecer | Kehoe, Patrick G. | Rodriguez-Rodriguez, Eloy | Bullido, Maria J | Ikram, M. Arfan | Smith, A. David | Lehmann, Donald J.
Article Type: Research Article
Abstract: Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer’s disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF , DBH , and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern …Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1–1.2, p = 0.005–0.3), an effect size that was consistent in the Northern European (OR = 1.1–1.2, p = 0.002–0.8) but not the smaller Spanish (OR = 0.8–1.6, p = 0.4–1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3–1.5 p = 0.002–0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2–1.3, p = 0.007–0.00008) than men (OR = 0.9–1.0, p = 0.3–0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women. Show more
Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, dopamine beta-hydroxylase, epistasis, genetics, neurotrophins, Sortilin
DOI: 10.3233/JAD-181116
Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1535-1547, 2019
Replication of BIN1 Association with Alzheimer's Disease and Evaluation of Genetic Interactions
Authors: Carrasquillo, Minerva M. | Belbin, Olivia | Hunter, Talisha A. | Ma, Li | Bisceglio, Gina D. | Zou, Fanggeng | Crook, Julia E. | Pankratz, V. Shane | Sando, Sigrid B. | Aasly, Jan O. | Barcikowska, Maria | Wszolek, Zbigniew K. | Dickson, Dennis W. | Graff-Radford, Neill R. | Petersen, Ronald C. | Morgan, Kevin | for the Alzheimer's Research Trust Consortium (ART) | Younkin, Steven G.
Article Type: Research Article
Abstract: The most recent late-onset Alzheimer's disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 × 10−11 ) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 × 10−9 ). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully …replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR = 1.17, p = 1.1 × 10−4 ) comparable to that previously reported (OR = 1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p = 0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p = 3.8 × 10−20 ). We also tested for epistatic interaction between these variants and APOE ε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1: rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further. Show more
Keywords: Alzheimer's disease, case-control studies, heterogeneity, late onset, meta-analysis
DOI: 10.3233/JAD-2011-101932
Citation: Journal of Alzheimer's Disease, vol. 24, no. 4, pp. 751-758, 2011
A Multi-Center Study of ACE and the Risk of Late-Onset Alzheimer's Disease
Authors: Belbin, Olivia | Brown, Kristelle | Shi, Hui | Medway, Christopher | Abraham, Richard | Passmore, Peter | Mann, David | Smith, A. David | Holmes, Clive | McGuinness, Bernadette | Craig, David | Warden, Donald | Heun, Reinhard | Kölsch, Heike | Love, Seth | Kalsheker, Noor | Williams, Julie | Owen, Michael J. | Carrasquillo, Minerva | Younkin, Steven | Morgan, Kevin | Kehoe, Patrick G.
Article Type: Research Article
Abstract: A key pathological feature of late-onset Alzheimer's disease (LOAD) is the abnormal extracellular accumulation of the amyloid-β (Aβ) peptide. Thus, altered Aβ degradation could be a major contributor to the development of LOAD. Variants in the gene encoding the Aβ-degrading enzyme, angiotensin-1 converting enzyme (ACE) therefore represent plausible candidates for association with LOAD pathology and risk. Following Alzgene meta-analyses of all published case-control studies, the ACE variants rs4291 and rs1800764 showed significant association with LOAD risk. Furthermore ACE haplotypes are associated with both plasma ACE levels and LOAD risk. We tested three ACE variants (rs4291, rs4343, and rs1800764) for association …with LOAD in ten Caucasian case-control populations (n = 8,212). No association was found using multiple logistic models (all p > 0.09). We found no population heterogeneity (all p > 0.38) or evidence for association with LOAD risk following meta-analysis of the ten populations for rs4343 (OR = 1.00), rs4291 (OR = 0.97), or rs1800764 (OR = 0.99). Although we found no haplotypic association in our complete dataset (p = 0.51), a significant global haplotypic p-value was observed in one population (p = 0.007) due to an association of the H3 haplotype (OR = 0.72, p = 0.02) and a trend towards an association of H4 (OR = 1.38, p = 0.09) and H7 (OR = 2.07, p = 0.08) although these did not survive Bonferroni correction. Previously reported associations of ACE variants with LOAD will be diminished following this study. At best, ACE variants have modest effect sizes, which are likely part of a complex interaction between genetic, phenotypic and pharmacological effects that would be undetected in traditional case-control studies. Show more
Keywords: Alzheimer's disease, angiotensin-1 converting enzyme, haplotype, heterogeneity, late onset, meta-analysis
DOI: 10.3233/JAD-2011-101914
Citation: Journal of Alzheimer's Disease, vol. 24, no. 3, pp. 587-597, 2011