- Email: [email protected]
A DYRK1A polymorphism and dementia
S192
Poster Presentations P1
Background: Diagnostic misclassification has consistently been reported in complex diseases such as AD. The ‘‘gold standard’’ for a definitive diagnosis of AD is performed by neuropathological examination post-mortem. We stratified our AD families previously reported in a genome-wide scan, into a subset of 24 families with at least one autopsy-confirmed AD case per family. Methods: The total sample set included 78 patients and 60 unaffected siblings and spouses. The range of cases per family was 2-8 (mean 3.5) and the average AAO was 68.8 (range 42-84) years. A linkage analysis of the 24 pedigrees was performed showing a significant spt LOD score of 4.4 in 8q24, followed by fine mapping under the linkage peak. First by microsatellites in the same 24 families with additional siblings and secondly by gene-wide SNP genotyping of 22 selected genes in an extended family material consisting of 30 families (the original 24 plus six novel families).The SNP data were first subjected to a family-based association analysis using PLINK, followed by linkage analysis using a combination of SNP genotypes and the already acquired microsatellite genotypes. We have also sequenced the translated parts of two candidate genes in the linked region; NDRG1 and KHDRBS3. Results: A suggestive linkage was obtained at peak marker rs6577853 (mpt LOD ¼ 2.4) and a spt LOD of 3.2 at D8S1746. Twelve SNPs with p-values less than 0.05 were obtained in the PLINK analysis; however none of the SNPs survived correction for multiple testing. The lowest obtained p-value was recorded for the intronic tagSNP rs2252696 in the SLA/TG region. No mutation was identified in the sequence analysis of NDRG1 and KHDRBS3. Recombination events were observed under the linkage peak in five of the 30 analyzed families. These recombinations can be utilized to identify the smallest shared chromosomal interval; in this case a 3.2 Mb region flanked by markers D8S256 and D8S1761. Conclusions: A handful genes are located in the interval between the peak markers obtained in the mpt and spt linkage analysis, supported by the observed recombinations, and none of the genes have previously been implicated in AD.
P1-064
SNPS ASSOCIATED WITH CSF TAU LEVELS MODIFY RATE OF PROGRESSION IN ALZHEIMER’S DISEASE
Carlos Cruchaga1, John S. Kauwe2, Kevin Mayo1, Sarah Bertelsen1, Petra Nowotny1, Aarti R. Shah1, Richard Abraham3, Paul Hollingworth3, Denise Harold3, Michael J. Owen3, Julie Williams3, Simon Lovestone4, The Alzheimer’s Disease Neuroimaging Initiative, John C. Morris1, Anne M. Fagan1, David M. Holtzman1, Alison M. Goate1, 1Washington University School of Medicine, St. Louis, MO, USA; 2Department of Biology, Brigham Young University, Provo, UT, USA; 3Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom; 4Institute of Psychiatry, Kings College, London, United Kingdom. Contact e-mail: [email protected] Background: Quantitative traits such as CSF tau levels offer more power than case-control tests in identifying genes implicated in Alzheimer’s disease (AD). In our previous studies we found several SNPs, located in the genes encoding the regulatory subunit of the protein phosphatase 2B (PPP3R1), and the microtubule-associated protein tau (MAPT) gene, that are associated with CSF tau levels. In this study we tested the impact of these SNPs on risk for AD, age at onset and rate of disease progression Methods: Allelic and genotypic association with risk for AD was tested using a Fisher’s exact test. Association with age at onset was carried out using Kaplan-Meier curves and a log-rank test. We used a mixed linear model to determine whether there are differences in the rate of progression as a function of genotype. Progression of disease was measured by annual change in CDR sum of boxes (CDRSB). Results: We found no association between rs1868402 and risk for AD or age at onset. However, individuals homozygous for the rs1868402 allele associated with higher CSF tau levels showed a six fold faster change in CDR-SB than individuals of other genotypes (p ¼ 0.0026). We found significant epistasis between rs1868402 (PPP3R1) and rs3785883 (MAPT) (P ¼ 4.00310-04). In contrast we found that the e4 allele of APOE, which is strongly associated with CSF AB42 levels, is not associated with progression rate in these samples. Conclusions: Our analyses suggest that genetic vari-
ants associated with CSF Ab42 levels also influence risk and age at onset (as in the case of APOE) but variants associated with CSF tau and ptau181 levels may have a greater impact on rate of progression. Variants that influence disease progression may have significant clinical benefit. For example, these variants have the potential to predict more accurately the time from diagnosis to functional impairment that may require nursing home placement. Stratification of samples by such SNPs will enable cheaper and more efficient clinical trials by selecting individuals expected to have faster rates of progression.
P1-065
IRON/COPPER METABOLISM: NEW IMPLICATIONS IN ALZHEIMER’S DISEASE
ˆ ngela C. Crespo2, Liliana Marques3, Alexandre de Mendonc¸a1, A 1 ˆ ngela Timo´teo5, Erica Marcelino , Carolina Maruta4, So´nia Costa5, A Frederico Simo˜es Couto1, Ana Herrero5, Ana Verdelho1, Manuela Guerreiro4, Cristina Costa5, Luciana Costa3, Madalena Martins1,2, 1 Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal; 2Instituto Gulbenkian de Cieˆncia, Oeiras, Portugal; 3 Instituto Nacional de Sau´de Dr. Ricardo Jorge, Lisbon, Portugal; 4Laborato´rio de Estudos de Linguagem, Instituto de Medicina Molecular, Lisbon, Portugal; 5Servic¸o de Neurologia, Hospital Fernando Fonseca, Lisbon, Portugal. Contact e-mail: [email protected] Background: The distinction between normal aging and Alzheimer’s Disease (AD) is a relevant step to combat this disease efficiently. In this study, we seek to further investigate the implication of the redox-active biometals, copper (Cu) and iron (Fe) imbalance in the oxidative injury hypothesis of AD pathogenesis. Furthermore, we propose to overcome the heterogeneity issue in AD through the evaluation of epistatic effects among candidate genes and specific endophenotypes involved in Fe/Cu homeostasis. Methods: We further investigated the oxidative injury hypothesis by: (I) comparing serum biochemical markers of Fe/Cu metabolism in a sample of 73 AD patients and 60 healthy controls; (II) testing, in the same sample, a set of Fe/Cu metabolism-related genes and APOE for association with AD. Genetic analysis was performed through high density SNP genotyping of the candidate genes SLC11A2, SLC40A1, TfR2, Tf, HFE, IRP1, IRP2, CYBRD1 and CP. Biochemical analysis was assessed for: serum Fe, total Fe binding capacity, transferrin levels, transferrin saturation, ferritin levels, CP and its oxidase activity. Results: Significant differences were found between female AD patients and controls for serum Fe concentration (71.02 6 22.34 mg/dL and 86.38 6 20.80 mg/dL, respectively, p ¼ 0.001) and transferrin saturation (22.29 6 7.89 % and 26.21 6 6.24 %, respectively, p ¼ 0.007). A significant association with AD was found for TF - transferrin gene (p ¼ 0.0082) and for the first time for SLC40A1 - ferroportin (Fpn) gene (p ¼ 0.0355). APOEe4 was also significantly associated with AD (p ¼ 0.0004), in agreement with previous studies. Conclusions: We hypothesize that the lower serum Fe concentration observed in AD patients can be due to impaired Fe excretion from cells, since Fpn is the only known Fe exporter in mammalian cells. The intracellular accumulation of Fe, particularly in the brain, where Fpn is also expressed, would lead to a rise in oxidative damage, contributing to the AD physiopathology. Further research is demanded in a greater sample to confirm the results obtained in this pilot study. Noteworthy, an integrative approach was followed to deal with heterogeneity in this complex disorder, and new directions were raised related to the study of the involvement of Fe metabolism in AD.
P1-066
A DYRK1A POLYMORPHISM AND DEMENTIA
Emma L. Jones1, Sally Sharp2, Dag Aarsland3, Elisabet Londos4, Clive Ballard1, 1King’s College London, London, United Kingdom; 2University College London, London, United Kingdom; 3Clinical Neuroscience Research, Stavanger University Hospital, Stavanger, Norway; 4Clinical Memory Research Unit, Department of Clinical Sciences Malmo¨, Lund University, Malmo, Sweden. Contact e-mail: [email protected] Background: People with Down syndrome (DS) usually develop Alzheimer’s disease (AD) with an early age of onset. DYRK1A is a kinase located on
Poster Presentations P1 chromosome 21 which can phosphorylate tau at Thr212; a residue found to be hyperphosphorylated in pathological tau. DYRK1A is expressed at higher levels in the presence of increasing levels of Ab, whilst overexpression of DYRK1A leads to increases in phosphorylated APP and Ab. Therefore, DYRK1A can potentially play roles in the development of both Ab and tau pathologies in AD. A potential risk haplotype for Alzheimer’s disease (AD) has been found in DYRK1A and in this study we examine the impact of DYRK1A genetics upon AD in people with DS, and other types of dementia. Methods: Tissue samples were available from 109 controls and 351 individuals with the following diagnoses - DS, AD, dementia with lewy bodies (DLB), Parkinson’s disease dementia (PDD), vascular dementia (VaD), VaD + AD, stroke but no dementia (SND) and frontotemporal dementia (FTD). DNA from blood or brain was extracted using a commercially available kit (DNeasy tissue kit, Qiagen). The rs8126696 polymorphism of DYRK1A was genotyped using a validated Taqman SNP genotyping assay. Results: Less people who are homozygous for the rs8126696 T allele have dementia than those with 2 C alleles (p ¼ 0.048). In addition, amongst people with Down’s syndrome the age of onset of dementia was significantly lower in people homozygous for the T allele than those with 1 or more C alleles (p ¼ 0.008). Examining specific dementias, more patients with VaD who had the CC genotype also had AD pathology than those with the TT genotype (p ¼ 0.04), but there was no difference in the distribution of CC and TT genotypes between AD patients and controls (p ¼ 0.22). Conclusions: DYRK1A may be important in the progression of certain stages of dementia, such as the acceleration of onset of cognitive decline and the development of Ab pathology alongside vascular pathology. Further examination of the impact upon the development of other defining pathological changes, such as tangle pathology, is required to interpret further DYRK1A’s role in dementia.
P1-067
IMPLICATIONS AND FREQUENCY OF APP, PSEN1, PSEN2, GRN AND MAPT MUTATION IN A WELLCHARACTERIZED SERIES OF LATE-ONSET ALZHEIMER FAMILIES
Carlos Cruchaga1, Sumi Chakraverty1, Gabe Haller1, Mayo Kevin1, Francesco L. Vallania1, Mitra D. Robi1, NIA-LOAD/NCRAD Family Study Consortium, Tom D. Bird2, Ramo´n Diaz-Arrestia3, Bradley Boeve4, Boeve Bradley5, Neill R. Graff-Radford6, Richard Mayeux7, Alison Goate1, 1 Washington University School of Medicine, St. Louis, MO, USA; 2VA Medical Center and Departments of Neurology and Medicine, University of Washington, Seattle, WA, USA; 3Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 4Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA; 5Department of Neurology Mayo Clinic, Rochester, MN, USA; 6Department of Neurology, Mayo Clinic, Jacksonville, FL, USA; 7Institute for Research on Alzheimer’s Disease and the Aging Brain. Columbia University, New York, NY, USA. Contact e-mail: [email protected] Background: Familial Alzheimer disease (FAD) is characterized by an early onset (<60 years) and an autosomal dominant pattern of inheritance with high penetrance. Mutations in three genes, APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been found as cause of FAD. To date 173 mutations in PSEN1, 26 in APP and 14 in PSEN2 have been identified in FAD cases. In addition, mutations in the progranulin gene (GRN), and microtubule-associated protein tau (MAPT) which cause frontotemporal dementia, can present clinically with an AD phenotype. Although a documented PSEN1 mutation has been reported in a family with a mean age at onset of 69yrs the implications and frequency of mutation in these genes in densely affected late-onset AD (LOAD) families has been less well studied. Methods: We have used second generation sequencing technology and pool DNA approach to screen APP, PSEN1, PSEN2, MAPT and GRN for pathogenic mutations in 448 clinically diagnosed LOAD families with four or more affected members, recruited by the NIA Alzheimer’s Diseases Genetics Initiative. Results: We have found several known pathogenic mutations in PSEN1 and GRN and new non-synonymous changes in APP, PSEN1, GRN and MAPT, that could also be
S193
pathogenic. Conclusions: Although mutations in APP, PSEN1, and PSEN2 have been linked to early-onset AD, here we demonstrated that mutations in these genes are also present in late-onset AD families. We have confirmed that individuals with pathogenic mutations in GRN can present clinically with an AD phenotype, and therefore this gene should be screened for pathogenic mutations in clinically diagnosed LOAD families. Removal of families with a known cause of dementia from this and other datasets should facilitate the identification of novel AD genes in these densely affected families.
P1-068
COGNITIVE PHENOTYPES IN ALZHEIMER’S DISEASE AND INSULIN DEGRADING ENZYME GENE VARIANTS
Emma R. L. C. Vardy1, Kristelle Brown2, Cheryl L. Stopford1, Noor Kalsheker2, David Neary1, David M. A. Mann1, Kevin Morgan2, Julie S. Snowden1, 1University of Manchester, Manchester, United Kingdom; 2University of Nottingham, Nottingham, United Kingdom. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is usually considered as a condition that initially affects memory, though clinical presentation is variable. ‘Typically’ AD presents with a constellation of memory and other cortical deficits. Other cognitive phenotypes exhibiting more circumscribed deficits have been identified. Such clinical distinctions are topographically mirrored on neuroimaging. Those factors that influence phenotypic variation within the diagnosis of AD are poorly understood, though family history and Apolipoprotein E (APOE) e4 allele status are closely associated. We have previously found that APOE e4 allele is associated with AD presentations predominantly affecting memory, and thereby temporal lobe dysfunction. Pathogenetically, ApoE protein may act in the brain through facilitating amyloidosis. We explored the hypothesis that other genetic factors favouring b-amyloid deposition, such as the insulin degrading enzyme gene (IDE), may likewise bear phenotypic influence. Methods: 181 subjects with a diagnosis of probable AD were included in this study. All subjects had detailed clinical history, neurological examination and neuropsychological profiling. Subjects were classified, according to data obtained at time of initial clinical referral, into one of the following cognitive phenotype categories: typical (TP), amnestic or memory/semantic (Limbic/LT), language (Lang), visual or apraxic (Post) and frontal. Subjects were genotyped for 10 single nucleotide polymorphisms for IDE, representing those tagging variants identified in previously published studies. Results: For analytical purposes, the few subjects with a frontal presentation (n ¼ 3) were excluded. Of the 10 IDE polymorphisms studied, only rs17875327IDE was associated with a particular cognitive phenotype. Homozygosity for the T-allele occurred in 93% of Limbic/LT, 88% Lang, 80% of TP, and 63% of Post cases. The frequency of the TT homozygote in limbic/LT cases, compared to other phenotypic presentations, was statistically significant (p < 0.05). Conclusions: We have previously shown that possession of APOE e4 allele is predominant in the Limbic/LT group, compared to other cognitive phenotypes. Here we show a polymorphism in the IDE gene to be similarly associated with cognitive phenotypes predominantly affecting memory. This suggests that the APOE e4 allele and this IDE polymorphism might act synergistically to drive an underlying pathogenic mechanism which favours b-amyloid deposition in vulnerable temporal lobe structures such as the hippocampus.
P1-069
A STUDY ON THE ASSOCIATION BETWEEN CHOLINEACETYLTRANSFERASE (CHAT) POLYMORPHISM AND TREATMENT RESPONSES OF ACETYLCHOLINESTERASE INHIBITORS IN ALZHEIMER PATIENTS
Mankil Seo, Hongseong Medical Center, Chungcheong Namdo, Korea. Contact e-mail: [email protected] Background: Cholineacetyltranferase(ChAT) is the special enzyme responsible for biosynthesis of acetylcholine that is involved in memory, learning,
Poster Presentations P1
Background: Diagnostic misclassification has consistently been reported in complex diseases such as AD. The ‘‘gold standard’’ for a definitive diagnosis of AD is performed by neuropathological examination post-mortem. We stratified our AD families previously reported in a genome-wide scan, into a subset of 24 families with at least one autopsy-confirmed AD case per family. Methods: The total sample set included 78 patients and 60 unaffected siblings and spouses. The range of cases per family was 2-8 (mean 3.5) and the average AAO was 68.8 (range 42-84) years. A linkage analysis of the 24 pedigrees was performed showing a significant spt LOD score of 4.4 in 8q24, followed by fine mapping under the linkage peak. First by microsatellites in the same 24 families with additional siblings and secondly by gene-wide SNP genotyping of 22 selected genes in an extended family material consisting of 30 families (the original 24 plus six novel families).The SNP data were first subjected to a family-based association analysis using PLINK, followed by linkage analysis using a combination of SNP genotypes and the already acquired microsatellite genotypes. We have also sequenced the translated parts of two candidate genes in the linked region; NDRG1 and KHDRBS3. Results: A suggestive linkage was obtained at peak marker rs6577853 (mpt LOD ¼ 2.4) and a spt LOD of 3.2 at D8S1746. Twelve SNPs with p-values less than 0.05 were obtained in the PLINK analysis; however none of the SNPs survived correction for multiple testing. The lowest obtained p-value was recorded for the intronic tagSNP rs2252696 in the SLA/TG region. No mutation was identified in the sequence analysis of NDRG1 and KHDRBS3. Recombination events were observed under the linkage peak in five of the 30 analyzed families. These recombinations can be utilized to identify the smallest shared chromosomal interval; in this case a 3.2 Mb region flanked by markers D8S256 and D8S1761. Conclusions: A handful genes are located in the interval between the peak markers obtained in the mpt and spt linkage analysis, supported by the observed recombinations, and none of the genes have previously been implicated in AD.
P1-064
SNPS ASSOCIATED WITH CSF TAU LEVELS MODIFY RATE OF PROGRESSION IN ALZHEIMER’S DISEASE
Carlos Cruchaga1, John S. Kauwe2, Kevin Mayo1, Sarah Bertelsen1, Petra Nowotny1, Aarti R. Shah1, Richard Abraham3, Paul Hollingworth3, Denise Harold3, Michael J. Owen3, Julie Williams3, Simon Lovestone4, The Alzheimer’s Disease Neuroimaging Initiative, John C. Morris1, Anne M. Fagan1, David M. Holtzman1, Alison M. Goate1, 1Washington University School of Medicine, St. Louis, MO, USA; 2Department of Biology, Brigham Young University, Provo, UT, USA; 3Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom; 4Institute of Psychiatry, Kings College, London, United Kingdom. Contact e-mail: [email protected] Background: Quantitative traits such as CSF tau levels offer more power than case-control tests in identifying genes implicated in Alzheimer’s disease (AD). In our previous studies we found several SNPs, located in the genes encoding the regulatory subunit of the protein phosphatase 2B (PPP3R1), and the microtubule-associated protein tau (MAPT) gene, that are associated with CSF tau levels. In this study we tested the impact of these SNPs on risk for AD, age at onset and rate of disease progression Methods: Allelic and genotypic association with risk for AD was tested using a Fisher’s exact test. Association with age at onset was carried out using Kaplan-Meier curves and a log-rank test. We used a mixed linear model to determine whether there are differences in the rate of progression as a function of genotype. Progression of disease was measured by annual change in CDR sum of boxes (CDRSB). Results: We found no association between rs1868402 and risk for AD or age at onset. However, individuals homozygous for the rs1868402 allele associated with higher CSF tau levels showed a six fold faster change in CDR-SB than individuals of other genotypes (p ¼ 0.0026). We found significant epistasis between rs1868402 (PPP3R1) and rs3785883 (MAPT) (P ¼ 4.00310-04). In contrast we found that the e4 allele of APOE, which is strongly associated with CSF AB42 levels, is not associated with progression rate in these samples. Conclusions: Our analyses suggest that genetic vari-
ants associated with CSF Ab42 levels also influence risk and age at onset (as in the case of APOE) but variants associated with CSF tau and ptau181 levels may have a greater impact on rate of progression. Variants that influence disease progression may have significant clinical benefit. For example, these variants have the potential to predict more accurately the time from diagnosis to functional impairment that may require nursing home placement. Stratification of samples by such SNPs will enable cheaper and more efficient clinical trials by selecting individuals expected to have faster rates of progression.
P1-065
IRON/COPPER METABOLISM: NEW IMPLICATIONS IN ALZHEIMER’S DISEASE
ˆ ngela C. Crespo2, Liliana Marques3, Alexandre de Mendonc¸a1, A 1 ˆ ngela Timo´teo5, Erica Marcelino , Carolina Maruta4, So´nia Costa5, A Frederico Simo˜es Couto1, Ana Herrero5, Ana Verdelho1, Manuela Guerreiro4, Cristina Costa5, Luciana Costa3, Madalena Martins1,2, 1 Neurological Clinical Research Unit, Instituto de Medicina Molecular, Lisbon, Portugal; 2Instituto Gulbenkian de Cieˆncia, Oeiras, Portugal; 3 Instituto Nacional de Sau´de Dr. Ricardo Jorge, Lisbon, Portugal; 4Laborato´rio de Estudos de Linguagem, Instituto de Medicina Molecular, Lisbon, Portugal; 5Servic¸o de Neurologia, Hospital Fernando Fonseca, Lisbon, Portugal. Contact e-mail: [email protected] Background: The distinction between normal aging and Alzheimer’s Disease (AD) is a relevant step to combat this disease efficiently. In this study, we seek to further investigate the implication of the redox-active biometals, copper (Cu) and iron (Fe) imbalance in the oxidative injury hypothesis of AD pathogenesis. Furthermore, we propose to overcome the heterogeneity issue in AD through the evaluation of epistatic effects among candidate genes and specific endophenotypes involved in Fe/Cu homeostasis. Methods: We further investigated the oxidative injury hypothesis by: (I) comparing serum biochemical markers of Fe/Cu metabolism in a sample of 73 AD patients and 60 healthy controls; (II) testing, in the same sample, a set of Fe/Cu metabolism-related genes and APOE for association with AD. Genetic analysis was performed through high density SNP genotyping of the candidate genes SLC11A2, SLC40A1, TfR2, Tf, HFE, IRP1, IRP2, CYBRD1 and CP. Biochemical analysis was assessed for: serum Fe, total Fe binding capacity, transferrin levels, transferrin saturation, ferritin levels, CP and its oxidase activity. Results: Significant differences were found between female AD patients and controls for serum Fe concentration (71.02 6 22.34 mg/dL and 86.38 6 20.80 mg/dL, respectively, p ¼ 0.001) and transferrin saturation (22.29 6 7.89 % and 26.21 6 6.24 %, respectively, p ¼ 0.007). A significant association with AD was found for TF - transferrin gene (p ¼ 0.0082) and for the first time for SLC40A1 - ferroportin (Fpn) gene (p ¼ 0.0355). APOEe4 was also significantly associated with AD (p ¼ 0.0004), in agreement with previous studies. Conclusions: We hypothesize that the lower serum Fe concentration observed in AD patients can be due to impaired Fe excretion from cells, since Fpn is the only known Fe exporter in mammalian cells. The intracellular accumulation of Fe, particularly in the brain, where Fpn is also expressed, would lead to a rise in oxidative damage, contributing to the AD physiopathology. Further research is demanded in a greater sample to confirm the results obtained in this pilot study. Noteworthy, an integrative approach was followed to deal with heterogeneity in this complex disorder, and new directions were raised related to the study of the involvement of Fe metabolism in AD.
P1-066
A DYRK1A POLYMORPHISM AND DEMENTIA
Emma L. Jones1, Sally Sharp2, Dag Aarsland3, Elisabet Londos4, Clive Ballard1, 1King’s College London, London, United Kingdom; 2University College London, London, United Kingdom; 3Clinical Neuroscience Research, Stavanger University Hospital, Stavanger, Norway; 4Clinical Memory Research Unit, Department of Clinical Sciences Malmo¨, Lund University, Malmo, Sweden. Contact e-mail: [email protected] Background: People with Down syndrome (DS) usually develop Alzheimer’s disease (AD) with an early age of onset. DYRK1A is a kinase located on
Poster Presentations P1 chromosome 21 which can phosphorylate tau at Thr212; a residue found to be hyperphosphorylated in pathological tau. DYRK1A is expressed at higher levels in the presence of increasing levels of Ab, whilst overexpression of DYRK1A leads to increases in phosphorylated APP and Ab. Therefore, DYRK1A can potentially play roles in the development of both Ab and tau pathologies in AD. A potential risk haplotype for Alzheimer’s disease (AD) has been found in DYRK1A and in this study we examine the impact of DYRK1A genetics upon AD in people with DS, and other types of dementia. Methods: Tissue samples were available from 109 controls and 351 individuals with the following diagnoses - DS, AD, dementia with lewy bodies (DLB), Parkinson’s disease dementia (PDD), vascular dementia (VaD), VaD + AD, stroke but no dementia (SND) and frontotemporal dementia (FTD). DNA from blood or brain was extracted using a commercially available kit (DNeasy tissue kit, Qiagen). The rs8126696 polymorphism of DYRK1A was genotyped using a validated Taqman SNP genotyping assay. Results: Less people who are homozygous for the rs8126696 T allele have dementia than those with 2 C alleles (p ¼ 0.048). In addition, amongst people with Down’s syndrome the age of onset of dementia was significantly lower in people homozygous for the T allele than those with 1 or more C alleles (p ¼ 0.008). Examining specific dementias, more patients with VaD who had the CC genotype also had AD pathology than those with the TT genotype (p ¼ 0.04), but there was no difference in the distribution of CC and TT genotypes between AD patients and controls (p ¼ 0.22). Conclusions: DYRK1A may be important in the progression of certain stages of dementia, such as the acceleration of onset of cognitive decline and the development of Ab pathology alongside vascular pathology. Further examination of the impact upon the development of other defining pathological changes, such as tangle pathology, is required to interpret further DYRK1A’s role in dementia.
P1-067
IMPLICATIONS AND FREQUENCY OF APP, PSEN1, PSEN2, GRN AND MAPT MUTATION IN A WELLCHARACTERIZED SERIES OF LATE-ONSET ALZHEIMER FAMILIES
Carlos Cruchaga1, Sumi Chakraverty1, Gabe Haller1, Mayo Kevin1, Francesco L. Vallania1, Mitra D. Robi1, NIA-LOAD/NCRAD Family Study Consortium, Tom D. Bird2, Ramo´n Diaz-Arrestia3, Bradley Boeve4, Boeve Bradley5, Neill R. Graff-Radford6, Richard Mayeux7, Alison Goate1, 1 Washington University School of Medicine, St. Louis, MO, USA; 2VA Medical Center and Departments of Neurology and Medicine, University of Washington, Seattle, WA, USA; 3Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 4Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA; 5Department of Neurology Mayo Clinic, Rochester, MN, USA; 6Department of Neurology, Mayo Clinic, Jacksonville, FL, USA; 7Institute for Research on Alzheimer’s Disease and the Aging Brain. Columbia University, New York, NY, USA. Contact e-mail: [email protected] Background: Familial Alzheimer disease (FAD) is characterized by an early onset (<60 years) and an autosomal dominant pattern of inheritance with high penetrance. Mutations in three genes, APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been found as cause of FAD. To date 173 mutations in PSEN1, 26 in APP and 14 in PSEN2 have been identified in FAD cases. In addition, mutations in the progranulin gene (GRN), and microtubule-associated protein tau (MAPT) which cause frontotemporal dementia, can present clinically with an AD phenotype. Although a documented PSEN1 mutation has been reported in a family with a mean age at onset of 69yrs the implications and frequency of mutation in these genes in densely affected late-onset AD (LOAD) families has been less well studied. Methods: We have used second generation sequencing technology and pool DNA approach to screen APP, PSEN1, PSEN2, MAPT and GRN for pathogenic mutations in 448 clinically diagnosed LOAD families with four or more affected members, recruited by the NIA Alzheimer’s Diseases Genetics Initiative. Results: We have found several known pathogenic mutations in PSEN1 and GRN and new non-synonymous changes in APP, PSEN1, GRN and MAPT, that could also be
S193
pathogenic. Conclusions: Although mutations in APP, PSEN1, and PSEN2 have been linked to early-onset AD, here we demonstrated that mutations in these genes are also present in late-onset AD families. We have confirmed that individuals with pathogenic mutations in GRN can present clinically with an AD phenotype, and therefore this gene should be screened for pathogenic mutations in clinically diagnosed LOAD families. Removal of families with a known cause of dementia from this and other datasets should facilitate the identification of novel AD genes in these densely affected families.
P1-068
COGNITIVE PHENOTYPES IN ALZHEIMER’S DISEASE AND INSULIN DEGRADING ENZYME GENE VARIANTS
Emma R. L. C. Vardy1, Kristelle Brown2, Cheryl L. Stopford1, Noor Kalsheker2, David Neary1, David M. A. Mann1, Kevin Morgan2, Julie S. Snowden1, 1University of Manchester, Manchester, United Kingdom; 2University of Nottingham, Nottingham, United Kingdom. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is usually considered as a condition that initially affects memory, though clinical presentation is variable. ‘Typically’ AD presents with a constellation of memory and other cortical deficits. Other cognitive phenotypes exhibiting more circumscribed deficits have been identified. Such clinical distinctions are topographically mirrored on neuroimaging. Those factors that influence phenotypic variation within the diagnosis of AD are poorly understood, though family history and Apolipoprotein E (APOE) e4 allele status are closely associated. We have previously found that APOE e4 allele is associated with AD presentations predominantly affecting memory, and thereby temporal lobe dysfunction. Pathogenetically, ApoE protein may act in the brain through facilitating amyloidosis. We explored the hypothesis that other genetic factors favouring b-amyloid deposition, such as the insulin degrading enzyme gene (IDE), may likewise bear phenotypic influence. Methods: 181 subjects with a diagnosis of probable AD were included in this study. All subjects had detailed clinical history, neurological examination and neuropsychological profiling. Subjects were classified, according to data obtained at time of initial clinical referral, into one of the following cognitive phenotype categories: typical (TP), amnestic or memory/semantic (Limbic/LT), language (Lang), visual or apraxic (Post) and frontal. Subjects were genotyped for 10 single nucleotide polymorphisms for IDE, representing those tagging variants identified in previously published studies. Results: For analytical purposes, the few subjects with a frontal presentation (n ¼ 3) were excluded. Of the 10 IDE polymorphisms studied, only rs17875327IDE was associated with a particular cognitive phenotype. Homozygosity for the T-allele occurred in 93% of Limbic/LT, 88% Lang, 80% of TP, and 63% of Post cases. The frequency of the TT homozygote in limbic/LT cases, compared to other phenotypic presentations, was statistically significant (p < 0.05). Conclusions: We have previously shown that possession of APOE e4 allele is predominant in the Limbic/LT group, compared to other cognitive phenotypes. Here we show a polymorphism in the IDE gene to be similarly associated with cognitive phenotypes predominantly affecting memory. This suggests that the APOE e4 allele and this IDE polymorphism might act synergistically to drive an underlying pathogenic mechanism which favours b-amyloid deposition in vulnerable temporal lobe structures such as the hippocampus.
P1-069
A STUDY ON THE ASSOCIATION BETWEEN CHOLINEACETYLTRANSFERASE (CHAT) POLYMORPHISM AND TREATMENT RESPONSES OF ACETYLCHOLINESTERASE INHIBITORS IN ALZHEIMER PATIENTS
Mankil Seo, Hongseong Medical Center, Chungcheong Namdo, Korea. Contact e-mail: [email protected] Background: Cholineacetyltranferase(ChAT) is the special enzyme responsible for biosynthesis of acetylcholine that is involved in memory, learning,