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Lan Tan - One of the best experts on this subject based on the ideXlab platform.
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association of alzheimer s disease risk variants on the PICALM gene with PICALM expression core biomarkers and feature neurodegeneration
Aging, 2020Co-Authors: Chenchen Tan, Lan Tan, Xipeng Cao, Alzheimers Disease Neuroimaging InitiativeAbstract:It is still unclear how PICALM mutations influence the risk of Alzheimer's disease (AD). We tested the association of AD risk variants on the PICALM gene with PICALM expression and AD feature endophenotypes. Bioinformatic methods were used to annotate the functionalities and to select the tag single nucleotide polymorphisms (SNPs). Multiple regressions were used to examine the cross-sectional and longitudinal influences of tag SNPs on cerebrospinal fluid (CSF) AD biomarkers and neurodegenerations. A total of 59 SNPs, among which 75% were reported in Caucasians, were associated with AD risk. Of these, 73% were linked to PICALM expression in the whole blood (p < 0.0001) and/or brain regions (p < 0.05). Eleven SNPs were selected as tag SNPs in Caucasians. rs510566 (T allele) was associated with decreased CSF ptau and ptau/abeta42 ratio. The G allele of rs1237999 and rs510566 was linked with greater reserve capacities of the hippocampus, parahippocampus, middle temporal lobe, posterior cingulate, and precuneus. The longitudinal analyses revealed four loci that could predict dynamic changes of CSF ptau and ptau/abeta42 ratio (rs10501610, p = 0.0001) or AD feature neurodegeneration (rs3851179, rs592297, and rs7480193, p < 0.005). Overall, the genetic, bioinformatic, and association studies tagged four SNPs (rs3851179, rs7480193, rs510566, and rs1237999) as the most prominent PICALM loci contributing to AD in Caucasians.
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the impact of PICALM genetic variations on reserve capacity of posterior cingulate in ad continuum
Scientific Reports, 2016Co-Authors: Huifu Wang, Lan Tan, Teng Jiang, Mengshan Tan, Xichen Zhu, Lin Tan, Chenchen Tan, Dan MiaoAbstract:Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer's disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly.
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the role of PICALM in alzheimer s disease
Molecular Neurobiology, 2015Co-Authors: Lan TanAbstract:Alzheimer's disease (AD) is a highly heritable disease (with heritability up to 76%) with a complex genetic profile of susceptibility, among which large genome-wide association studies (GWASs) pointed to the phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a susceptibility locus for late-onset Alzheimer's disease (LOAD) incidence. Here, we summarize the known functions of PICALM and discuss its genetic polymorphisms and their potential physiological effects associated with LOAD. Compelling data indicated that PICALM affects AD risk primarily by modulating production, transportation, and clearance of β-amyloid (Aβ) peptide, but other Aβ-independent pathways are discussed, including tauopathy, synaptic dysfunction, disorganized lipid metabolism, immune disorder, and disrupted iron homeostasis. Finally, given the potential involvement of PICALM in facilitating AD occurrence in multiple ways, it might be possible that targeting PICALM might provide promising and novel avenues for AD therapy.
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genetic variation in PICALM and alzheimer s disease risk in han chinese
Neurobiology of Aging, 2014Co-Authors: Teng Jiang, Lan Tan, Wei Zhang, Mengshan Tan, Huifu Wang, Yingli Wang, Xichen ZhuAbstract:The current study was conducted to investigate the association of phosphatidylinositol-binding clathrin assembly protein gene (PICALM) with late-onset Alzheimer's disease (LOAD) risk in Han Chinese. We first sequenced PICALM for variants in a small sample (n = 100), and the selected variants were then genotyped in a larger cohort (n = 2292). Sequencing analysis identified 16 variants within PICALM including 5 new variants with extreme low frequency in the northern Han Chinese population. However, in the subsequent genotyping, none showed a significant association with LOAD risk after Bonferroni correction. These findings implicate that PICALM might not play a major role in the genetic predisposition to LOAD in Han Chinese.
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genetic association of PICALM polymorphisms with alzheimer s disease in han chinese
Journal of the Neurological Sciences, 2011Co-Authors: Jinghui Song, Wei Zhang, Shiying Xuan, Lan TanAbstract:Abstract PICALM might play an important role in AD pathology through participating in altering synaptic vesicle cycling or APP endocytosis. A recent genome-wide study (GWAS) identified a single nucleotide polymorphism (SNP) rs3851179 in the 5′ to the PICALM gene strongly associated with Alzheimer's disease (AD) in Caucasians. In order to assess the involvement of the PICALM polymorphism in the risk of developing late-onset AD (LOAD), we analyzed the genotype and allele distributions of these three polymorphisms in 609 Han Chinese subjects. Our data showed no significant association between the PICALM rs3851179 polymorphism and LOAD (genotype distribution: P = 0.43; allele frequency: P = 0.25, odds ratio = 0.87, 95% confidence interval = 0.68 to 1.10), even after statistical adjustment for age, gender and apolipoprotein E (APOE) status. Our results suggest that the PICALM polymorphism may not play a major role in the development of LOAD in the Han Chinese population.
Marie-claude Potier - One of the best experts on this subject based on the ideXlab platform.
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PICALM reduction exacerbates tau pathology in a murine tauopathy model
Acta Neuropathologica, 2020Co-Authors: Kunie Ando, Valerie Suain, Robert De Decker, Cristina Vergara, Zehra Yilmaz, Salwa Mansour, Kristel Sleegers, Marie-ange Fisenne, Sarah Houben, Marie-claude PotierAbstract:Genome-wide association studies (GWAS) have identified PICALM as one of the most significant susceptibility loci for late-onset Alzheimer’s disease (AD) after APOE and BIN1 . PICALM is a clathrin-adaptor protein and plays critical roles in clathrin-mediated endocytosis and in autophagy. PICALM modulates brain amyloid ß (Aß) pathology and tau accumulation. We have previously reported that soluble PICALM protein level is reduced in correlation with abnormalities of autophagy markers in the affected brain areas of neurodegenerative diseases including AD, sporadic tauopathies and familial cases of frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) with mutations in the microtubule-associated protein tau ( MAPT ) gene. It remains unclarified whether in vivo PICALM reduction could either trigger or influence tau pathology progression in the brain. In this study, we confirmed a significant reduction of soluble PICALM protein and autophagy deficits in the post-mortem human brains of FTLD-tau- MAPT (P301L, S364S and L266V). We generated a novel transgenic mouse line named Tg30xPICALM+/− by crossing Tg30 tau transgenic mice with PICALM-haploinsufficient mice to test whether PICALM reduction may modulate tau pathology. While PICALM haploinsufficiency did not lead to any motor phenotype or detectable tau pathology in mouse brains, Tg30xPICALM+/− mice developed markedly more severe motor deficits than Tg30 by the age of 9 months. Tg30xPICALM+/− had significantly higher pathological tau levels in the brain, an increased density of neurofibrillary tangles compared to Tg30 mice and increased abnormalities of autophagy markers. Our results demonstrate that PICALM haploinsufficiency in transgenic Tg30 mice significantly aggravated tau pathologies and tau-mediated neurodegeneration, supporting a role for changes in PICALM expression as a risk/sensitizing factor for development of tau pathology and as a mechanism underlying the AD risk associated to PICALM.
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Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease
Neurobiology of Disease, 2016Co-Authors: Kunie Ando, Valerie Suain, Michele Authelet, Veronique Sazdovitch, Cristina Vergara, Zehra Yilmaz, Karen Tomimura, Marième Ndjim, Mounir Belkouch, Marie-claude PotierAbstract:Single nucleotide polymorphisms in PICALM, a key component of clathrin-mediated endocytosis machinery, have been identified as genetic susceptibility loci for late onset Alzheimer's disease (LOAD). We previously reported that PICALM protein levels were decreased in AD brains and that PICALM was co-localised with neurofibrillary tangles in LOAD, familial AD with PSEN1 mutations and Down syndrome. In the present study, we analysed PICALM expression, cell localisation and association with pathological cellular inclusions in other tauopathies and in non-tau related neurodegenerative diseases. We observed that PICALM was associated with neuronal tau pathology in Pick disease and in progressive supranuclear palsy (PSP) and co-localised with both 3R and 4R tau positive inclusions unlike in corticobasal degeneration (CBD) or in frontotemporal lobar degeneration (FTLD)-MAPT P301L. PICALM immunoreactivities were not detected in tau-positive tufted astrocytes in PSP, astrocytic plaques in CBD, Lewy bodies in Lewy body disease, diffuse type (LBD) and in TDP-43-positive inclusions in FTLD. In the frontal cortex in tauopathies, the ratio of insoluble to soluble PICALM was increased while the level of soluble PICALM was decreased and was inversely correlated with the level of phosphotau. PICALM decrease was also significantly correlated with increased LC3-II and decreased Beclin-1 levels in tauopathies and in non-tau related neurodegenerative diseases. These results suggest that there is a close relationship between abnormal PICALM processing, tau pathology and impairment of autophagy in human neurodegenerative diseases.
Natalya Ponomareva - One of the best experts on this subject based on the ideXlab platform.
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genetic association between alzheimer s disease risk variant of the PICALM gene and eeg functional connectivity in non demented adults
Frontiers in Neuroscience, 2020Co-Authors: Natalya Ponomareva, Tatiana Andreeva, Vitaly Fokin, Maria Protasova, Rodion Konovalov, Marina Krotenkova, Daria Malina, Andrey Mitrofanov, S N IllarioshkinAbstract:Genome wide association studies (GWAS) have identified and validated the association of the PICALM genotype with Alzheimer's disease (AD). The PICALM rs3851179 A allele is thought to have a protective effect, whereas the G allele appears to confer risk for AD. The influence of the PICALM genotype on brain functional connectivity in non-demented subjects remains largely unknown. We examined the association of the PICALM rs3851179 genotype with the characteristics of lagged linear connectivity (LLC) of resting EEG sources in 104 non-demented adults younger than 60 years of age. The EEG analysis was performed using exact low-resolution brain electromagnetic tomography (eLORETA) freeware (Pascual-Marqui et al., 2011). We found that the carriers of the A PICALM allele (PICALM AA and AG genotypes) had higher widespread interhemispheric LLC of alpha sources compared to the carriers of the GG PICALM allele. An exploratory correlation analysis showed a moderate positive association between the alpha LLC interhemispheric characteristics and the corpus callosum size and between the alpha interhemispheric LLC characteristics and the Luria word memory scores. These results suggest that the PICALM rs3851179 A allele provides protection against cognitive decline by facilitating neurophysiological reserve capacities in non-demented adults. In contrast, lower functional connectivity in carriers of the AD risk variant, PICALM GG, suggests early functional alterations in alpha rhythm networks.
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linking eegs alzheimer disease and the phosphatidylinositol binding clathrin assembly protein PICALM gene
2020Co-Authors: Natalya Ponomareva, Tatiana Andreeva, Vitaly Fokin, S N Illarioshkin, Evgeny RogaevAbstract:Abstract Genome-wide association studies have found an association between the PICALM genotype and Alzheimer disease. PICALM is involved in clathrin-mediated endocytosis and may contribute to the pathogenesis of Alzheimer disease through several pathways, including beta-amyloid production, impaired clearance of brain beta-amyloid and tau proteins, and synaptic dysfunction. The neurophysiological alterations in nondemented carriers of the PICALM GG rs3851179 risk variant for Alzheimer disease manifest in beta power elevation in resting electroencephalography during ageing, suggesting cortical disinhibition and hyperexcitability. PICALM GG carriers also exhibit delayed event-related potential P300 latency in ageing compared to PICALM GG noncarriers, indicating a decline in cognitive processing speed. The neurophysiological alterations may account for age-related cognitive deficits in PICALM GG carriers. We review current knowledge about the metabolic pathways of PICALM, the association of PICALM genotype with neurophysiological alterations during ageing, and we discuss the mechanisms underlying these alterations and their role in the pathogenesis of Alzheimer disease.
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genetic association between alzheimer s disease risk variant of the PICALM gene and auditory event related potentials in aging
Biochemistry, 2018Co-Authors: Natalya Ponomareva, Vitaly Fokin, S N Illarioshkin, Maria Protasova, T V Andreeva, Yu V Filippova, E P Kolesnikova, E I RogaevAbstract:Aging and genetic predisposition are major risk factors in age-related neurodegenerative disorders. The most common neurodegenerative disorder is Alzheimer's disease (AD). Genome-wide association studies (GWAS) have identified statistically significant association of the PICALM rs3851179 polymorphism with AD. The PICALM G allele increases the risk of AD, while the A allele has a protective effect. We examined the association of the PICALM rs3851179 polymorphism with parameters of the P3 component of auditory event-related potentials (ERPs) in 87 non-demented volunteers (age, 19-77 years) subdivided into two cohorts younger and older than 50 years of age. We found statistically significant association between the AD risk variant PICALM GG and increase in the P3 latency in subjects over 50 years old. The age-dependent increase in the P3 latency was more pronounced in the PICALM GG carriers than in the carriers of the PICALM AA and PICALM AG genotypes. The observed PICALM-associated changes in the neurophysiological processes indicate a decline in the information processing speed with aging due, probably, to neuronal dysfunction and subclinical neurodegeneration of the neuronal networks in the hippocampus and the frontal and parietal cortical areas. Such changes were less pronounced in the carriers of the PICALM gene A allele, which might explain the protective effect of this allele in the cognitive decline and AD development.
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quantitative eeg during normal aging association with the alzheimer s disease genetic risk variant in PICALM gene
Neurobiology of Aging, 2017Co-Authors: Natalya Ponomareva, Tatiana Andreeva, Vitaly Fokin, S N Illarioshkin, Maria Protasova, Daria Malina, Lef I Shagam, Andrey Goltsov, E I RogaevAbstract:Abstract Genome-wide association studies have identified novel risk variants for Alzheimer's disease (AD). Among these, a gene carrying one of the highest risks for AD is PICALM. The PICALM rs3851179 A allele is thought to have a protective effect, whereas the G allele appears to confer risk for AD. The influence of the PICALM genotype on brain function in nondemented subjects remains largely unknown. We examined the possible effect of the PICALM rs3851179 genotype on quantitative electroencephalography recording at rest in 137 nondemented volunteers (age range: 20–79 years) subdivided into cohorts of those younger than and those older than 50 years of age. The homozygous presence of the AD risk variant PICALM GG was associated with an increase in beta relative power, with the effect being more pronounced in the older cohort. Beta power elevation in resting-state electroencephalography has previously been linked to cortical disinhibition and hyperexcitability. The increase in beta relative power in the carriers of the AD risk PICALM GG genotype suggests changes in the cortical excitatory-inhibitory balance, which are heightened during normal aging.
Kunie Ando - One of the best experts on this subject based on the ideXlab platform.
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PICALM reduction exacerbates tau pathology in a murine tauopathy model
Acta Neuropathologica, 2020Co-Authors: Kunie Ando, Valerie Suain, Robert De Decker, Cristina Vergara, Zehra Yilmaz, Salwa Mansour, Kristel Sleegers, Marie-ange Fisenne, Sarah Houben, Marie-claude PotierAbstract:Genome-wide association studies (GWAS) have identified PICALM as one of the most significant susceptibility loci for late-onset Alzheimer’s disease (AD) after APOE and BIN1 . PICALM is a clathrin-adaptor protein and plays critical roles in clathrin-mediated endocytosis and in autophagy. PICALM modulates brain amyloid ß (Aß) pathology and tau accumulation. We have previously reported that soluble PICALM protein level is reduced in correlation with abnormalities of autophagy markers in the affected brain areas of neurodegenerative diseases including AD, sporadic tauopathies and familial cases of frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) with mutations in the microtubule-associated protein tau ( MAPT ) gene. It remains unclarified whether in vivo PICALM reduction could either trigger or influence tau pathology progression in the brain. In this study, we confirmed a significant reduction of soluble PICALM protein and autophagy deficits in the post-mortem human brains of FTLD-tau- MAPT (P301L, S364S and L266V). We generated a novel transgenic mouse line named Tg30xPICALM+/− by crossing Tg30 tau transgenic mice with PICALM-haploinsufficient mice to test whether PICALM reduction may modulate tau pathology. While PICALM haploinsufficiency did not lead to any motor phenotype or detectable tau pathology in mouse brains, Tg30xPICALM+/− mice developed markedly more severe motor deficits than Tg30 by the age of 9 months. Tg30xPICALM+/− had significantly higher pathological tau levels in the brain, an increased density of neurofibrillary tangles compared to Tg30 mice and increased abnormalities of autophagy markers. Our results demonstrate that PICALM haploinsufficiency in transgenic Tg30 mice significantly aggravated tau pathologies and tau-mediated neurodegeneration, supporting a role for changes in PICALM expression as a risk/sensitizing factor for development of tau pathology and as a mechanism underlying the AD risk associated to PICALM.
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Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease
Neurobiology of Disease, 2016Co-Authors: Kunie Ando, Valerie Suain, Michele Authelet, Veronique Sazdovitch, Cristina Vergara, Zehra Yilmaz, Karen Tomimura, Marième Ndjim, Mounir Belkouch, Marie-claude PotierAbstract:Single nucleotide polymorphisms in PICALM, a key component of clathrin-mediated endocytosis machinery, have been identified as genetic susceptibility loci for late onset Alzheimer's disease (LOAD). We previously reported that PICALM protein levels were decreased in AD brains and that PICALM was co-localised with neurofibrillary tangles in LOAD, familial AD with PSEN1 mutations and Down syndrome. In the present study, we analysed PICALM expression, cell localisation and association with pathological cellular inclusions in other tauopathies and in non-tau related neurodegenerative diseases. We observed that PICALM was associated with neuronal tau pathology in Pick disease and in progressive supranuclear palsy (PSP) and co-localised with both 3R and 4R tau positive inclusions unlike in corticobasal degeneration (CBD) or in frontotemporal lobar degeneration (FTLD)-MAPT P301L. PICALM immunoreactivities were not detected in tau-positive tufted astrocytes in PSP, astrocytic plaques in CBD, Lewy bodies in Lewy body disease, diffuse type (LBD) and in TDP-43-positive inclusions in FTLD. In the frontal cortex in tauopathies, the ratio of insoluble to soluble PICALM was increased while the level of soluble PICALM was decreased and was inversely correlated with the level of phosphotau. PICALM decrease was also significantly correlated with increased LC3-II and decreased Beclin-1 levels in tauopathies and in non-tau related neurodegenerative diseases. These results suggest that there is a close relationship between abnormal PICALM processing, tau pathology and impairment of autophagy in human neurodegenerative diseases.
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clathrin adaptor calm PICALM is associated with neurofibrillary tangles and is cleaved in alzheimer s brains
Acta Neuropathologica, 2013Co-Authors: Kunie Ando, Jean Pierre Brion, Virginie Stygelbout, Valerie Suain, Michele Authelet, Robert Dedecker, Anais Chanut, Pascale N Lacor, Jeremie Lavaur, Veronique SazdovitchAbstract:PICALM, a clathrin adaptor protein, plays important roles in clathrin-mediated endocytosis in all cell types. Recently, genome-wide association studies identified single nucleotide polymorphisms in PICALM gene as genetic risk factors for late-onset Alzheimer disease (LOAD). We analysed by western blotting with several anti-PICALM antibodies the pattern of expression of PICALM in human brain extracts. We found that PICALM was abnormally cleaved in AD samples and that the level of the uncleaved 65–75 kDa full-length PICALM species was significantly decreased in AD brains. Cleavage of human PICALM after activation of endogenous calpain or caspase was demonstrated in vitro. Immunohistochemistry revealed that PICALM was associated in situ with neurofibrillary tangles, co-localising with conformationally abnormal and hyperphosphorylated tau in LOAD, familial AD and Down syndrome cases. PHF-tau proteins co-immunoprecipitated with PICALM. PICALM was highly expressed in microglia in LOAD. These observations suggest that PICALM is associated with the development of AD tau pathology. PICALM cleavage could contribute to endocytic dysfunction in AD.
Jeancharles Lambert - One of the best experts on this subject based on the ideXlab platform.
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evidence of the association of bin1 and PICALM with the ad risk in contrasting european populations
Neurobiology of Aging, 2011Co-Authors: Jeancharles Lambert, Diana Zelenika, Mikko Hiltunen, Vincent Chouraki, Onofre Combarros, Maria J BullidoAbstract:Abstract Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer's disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15–1.38], p = 2.9 × 10−7, and OR = 0.80, 95% CI [0.74–0.88], p = 4.6 × 10−7, respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06–1.32], p = 2.0 × 10−3). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.
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the role of clusterin complement receptor 1 and phosphatidylinositol binding clathrin assembly protein in alzheimer disease risk and cerebrospinal fluid biomarker levels
Archives of General Psychiatry, 2011Co-Authors: Britmaren M Schjeide, Jeancharles Lambert, Cathrin Schnack, Christina M Lill, Julia Kirchheiner, Hayrettin Tumani, Markus Otto, Rudolph E Tanzi, Hans Lehrach, P AmouyelAbstract:Context: Two recent and simultaneously published genome-wide association studies independently implicated clusterin (CLU), complement receptor 1 (CR1), and phosphatidylinositol binding clathrin assembly protein (PICALM) as putative novel Alzheimer disease (AD) risk loci. Despite their strong statistical support, all 3 signals emerged from heterogeneous case-control populations and lack replication in different settings. Objective: To determine whether genetic variants in CLU, CR1, and PICALM confer risk for AD in independent data sets (n=4254) and to test the impact of these markers on cerebrospinal fluid (CSF)―Aβ42 and totaltau protein levels (n=425). Design: Genetic association study using family-based and case-control designs. Setting: Ambulatory or hospitalized care. Participants: Family samples originate from mostly multiplex pedigrees recruited at different centers in the United States (1245 families, 2654 individuals with AD, and 1175 unaffected relatives). Unrelated case-control subjects originate from 1 clinical center in Germany (214 individuals with AD and 211 controls). All subjects were of European descent. Main Outcome Measures: The association between 5 genetic variants in CLU, CR1, and PICALM and risk for AD, and the correlation between these 5 genetic variants and CSF-Aβ42 and tau levels. Results: All 3 investigated loci showed significant associations between risk for AD (1-tailed P values ranging from <.001 to .02) and consistent effect sizes and direction. For each locus, the overall evidence of association was substantially strengthened on meta-analysis of all available data (2-tailed P values ranging from 1.1 × 10 ―16 to 4.1 × 10 ―7 ). Of all markers tested, only rs541458 in PICALM was shown to have an effect on CSF protein levels, suggesting that the AD risk allele is associated with decreased CSF Aβ42 levels (2-tailed P=.002). Conclusions: This study provides compelling independent evidence that genetic variants in CLU, CR1, and PICALM are genetically associated with risk for AD. Furthermore, the CSF biomarker analyses provide a first insight into the potentially predominant pathogenetic mechanism(s) underlying the association between AD risk and PICALM.
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brief communication evidence of the association of bin1 and PICALM with the ad risk in contrasting european populations
2011Co-Authors: Jeancharles Lambert, Diana Zelenika, Mikko Hiltunen, Vincent Chouraki, Onofre Combarros, Maria J Bullido, Gloria Tognoni, Nathalie Fievet, Anne Boland, Beatrice ArosioAbstract:Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimer’s disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European
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genome wide analysis of genetic loci associated with alzheimer disease
JAMA, 2010Co-Authors: Sudha Seshadri, Annette L Fitzpatrick, Arfan M Ikram, Anita L Destefano, Vilmundur Gudnason, Merce Boada, Joshua C Bis, Albert V Smith, Minerva M Carassquillo, Jeancharles LambertAbstract:Context Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). Objectives To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35 000 persons (8371 AD cases). Design, Setting, and Participants In stage 1, we identified strong genetic associations (P < 10−3) in a sample of 3006 AD cases and 14 642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P<10−3. In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P<10−5. In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P<1.7×10−8. These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. Main Outcome Measure Presence of Alzheimer disease. Results Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45×10−9). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). Conclusions Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.