- Email: [email protected]
Genome-wide association study for cognitive decline
Tuesday, July 16, 2013: Poster Presentations: P3 analyses on the same traits in an extended set of the BASE-II dataset. Using an analysis pipeline recently developed by our group, we will assess whether any of the resulting memory-associated DNA-sequence variants are predicted to significantly interfere with miRNA function. As a proof of concept, we have begun detailed miRNA assessments on WWC1 (a.k.a. KIBRA), a gene previously reported to be implicated in episodic memory. Results: We performed association analyses on 33 single-nucleotide polymorphisms (SNPs) across all ten currently established AD loci and 14 episodic memory phenotypes in nearly 1,000 BASE-II participants aged 60 or older. The strongest signals were observed with SNPs in the APOE region (Pw1x10 -5), PICALM (P¼0.001) and ABCA7 (P¼0.02). Interestingly, these findings only became evident in a recognition test using a retention interval of one week, but not in tests using shorter intervals (<2.5 hours). Our in silico miRNA assessments currently reveal one SNP (rs77549240 located in hsa-miR-5197-3p) that may impact WWC1 protein expression. In vitro validation of this and other emerging findings is currently ongoing. Conclusions: Potential "memory effects" of SNPs located in established AD risk genes may only be detectable in paradigms with relatively long retention intervals that are more indicative of memory consolidation. Whether or not these and other polymorphisms associated with memory performance exert their effects via interfering with miRNA function will be assessed after completion of the GWAS analyses. P3-026
THE EFFECTS OF COGNITIVE RESERVE AND APOLIPOPROTEIN E ON HEALTHY COGNITIVE FUNCTION
David Ward1, Mathew Summers2, Nichole Saunders3, Michael Valenzuela4, Jeffery Summers5, Karen Ritchie6, Andrew Robinson7, James Vickers8, 1University of Tasmania/School of Medicine, Hobart/Tasmania, Australia; 2University of Tasmania/School of Psychology, Launceston, Tasmania, Australia; 3University of Tasmania, Hobart, Tasmania, Australia; 4University of Sydney/Sydney Medical School, Sydney, Australia; 5University of Tasmania/School of Psychology, Hobart, Australia; 6INSERM, Montpellier, France; 7University of Tasmania/School of Nursing and Midwifery, Hobart, Tasmania, Australia; 8University of Tasmania/School of Medicine, Hobart, Australia. Contact e-mail: David. [email protected] Background: Alzheimer’s disease research has identified environmental factors that delay the onset of dementia symptoms in the presence of disease processes. The beneficial effects of education, occupational status, and cognitively stimulating lifestyle activities are described through the theory of cognitive reserve, which are the individual differences in the efficient use and differential recruitment of brain networks due to life experience. Normally applied to pathological ageing, cognitive reserve has also been used to predict cognitive function in the face of normal age-related cognitive ageing, with mixed results. Similarly, apolipoprotein E is a genetic risk factor for late-onset Alzheimer’s disease that has shown mixed results when related to non-pathological cognitive function. The Tasmanian Healthy Brain Project is a prospective longitudinal study investigating such effects. Methods: Baseline data has been used to develop a cognitive reserve composite from a factor analysis of measures shown to modify dementia risk, investigate the relationship between ApoE allele status and cognitive reserve, and examine whether ApoE allele status and cognitive reserve interacted to predict non-pathological cognitive function. The study comprised 242 community-residing subjects (M age ¼ 61.20; SD ¼ 6.52) who undertook comprehensive neuropsychological examinations and genetic analysis. Results: Gel electrophoresis revealed an allelic distribution of 64.5% ε4 non-carrier and 35.5% ε4 carrier. Years of education, WAIS-III Full-scale IQ, and Lifetime of Experience scores were entered into principal components analysis that yielded a single significant cognitive reserve factor (eigenvalue ¼ 1.69) that explained 56.17% of the variance in the variables. Cognitive reserve factor z-scores were generated for subjects, with no significant difference in scores between ApoE ε4 carriers (M ¼ -.05; SD ¼ .94) and non-carriers (M ¼ .03; SD ¼ 1.03). Regression analysis showed cognitive reserve significantly predicted verbal memory performance in RAVLT total recall (r ¼ .17; p ¼ .03), Logical Memory delayed recall (r
P559
¼ .28; p < .01), and Letter Number Sequencing (r ¼ .22; p > .01) in ε4 non-carriers, whereas ε4 carriers did not possess such relationships. Conclusions: The results of this study demonstrated that cognitive reserve predicts ageing-susceptible verbal memory performance, but that the presence of this relationship was dependent on ε4 allele status. P3-027
OVEREXPRESSING HUMAN WILD- LRRK2 INCREASES SPATIAL RECOGNITION AND WORKING MEMORY PERFORMANCE IN MICE
Jun Ming Wang1, Samuel Adeosun2, Xu Hou2, Baoying Zheng2, University of Mississippi Medical Center, Jackson, Mississippi, United States; 2The University of Mississippi Medical Center, Jackson, Mississippi, United States. Contact e-mail: [email protected] 1
Background: The biological function of leucine-rich repeat kinase 2 (LRRK2), implicated in idiopathic Parkinson’s disease, has hitherto been elusive. Among other cellular and molecular mechanisms of learning and memory including neurite extension, synaptic functions, neurotransmitter release, LRRK2 has also been shown to play a role in regulating adult hippocampal neurogenesis. Even though LRRK2 seems to negatively regulate these processes, the implication of these findings in learning and memory is yet to be demonstrated. Methods: We carried out Y-Maze spontaneous alternation (spatial working memory) and novel arm discrimination (spatial recognition memory) tests in 7 month old female mice over-expressing the human wild type LRRK2 (LRRK2-Tg) and in non-transgenic agematched (Non-Tg) controls. Results: Surprisingly, LRRK2-Tg mice performed better than the Non-Tg mice in both tests. Exploration and locomotion were not different between the LRRK2-Tg and the Non-Tg mice. Conclusions: Despite its previously reported negative effects on neurite extension, synaptic functions, neurotransmitter release and neurogenesis, our currentresults suggest that LRRK2 modulate positively spatial memory behavior in mice. P3-028
GENOME-WIDE ASSOCIATION STUDY FOR COGNITIVE DECLINE
Lori Chibnik1, Lei Yu2, Towfique Raj3, Jishu Xu4, Nikolaos Patsopoulos4, Brendan Keenan5, Richard Sherva6, Sue Leurgans2, Deborah Blacker7, Robert Wilson8, Eric Reiman9, Matthew Huentelman10, The Alzheimer’s Disease Genetics Consortium11, Robert Green12, Lindsay Farrer6, Paul Crane13, David Weir14, Richard Mayeux15, Richard Lipton16, Gerard Schellenberg17, Denis Evans18, Philip De Jager1, David Bennett19, 1Brigham & Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States; 2Rush Alzheimer’s Disease Center, Chicago, Illinois, United States; 3Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States; 4Brigham & Women’s Hospital, Boston, Massachusetts, United States; 5Brigham and Women’s Hospital, Boston, Massachusetts, United States; 6Boston University, Boston, Massachusetts, United States; 7Massachusetts General Hospital/Harvard Medical School, Harvard School of Public Health, Charlestown, Massachusetts, United States; 8Rush University Medical Center, Chicago, Massachusetts, United States; 9Banner Alzheimer’s Institute, Phoenix, Arizona, United States; 10TGen, Phoenix, Arizona, United States; 11University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 12Harvard Medical School, Boston, Massachusetts, United States; 13University of Washington School of Medicine, Seattle, Washington, United States; 14Institute for Social Research, Ann Arbor, Michigan, United States; 15Columbia University, New York, New York, United States; 16Albert Einstein College of Medicine, Bronx, New York, United States; 17University of Pennsylvania, Philadelphia, Pennsylvania, United States; 18Rush University Medical Center, Chicago, Illinois, United States; 19Rush University Medical Center, Chicago, Illinois, United States. Contact e-mail: [email protected]. harvard.edu Background: Cognitive decline, especially decline in episodic memory, is the clinical hallmark of Alzheimer’s disease (AD) and known to start long before the onset of clinically diagnosed AD dementia. Thus, it may serve
P560
Tuesday, July 16, 2013: Poster Presentations: P3
as a useful quantitative phenotype for GWAS and other "omics" analyses. Methods: We included non-Hispanic White participants from four prospective community-based cohort studies (ROS, MAP, CHAP, EAS) who were non-demented at study entry and have at least two repeated measures of cognition. Within each cohort, individual cognitive tests were combined to form aggregate measures of global cognition and episodic memory. Genotype data from each cohort was quality controlled and imputed using 1000Genomes reference panel. We used linear mixed effects models to characterize individual paths of change in cognition, modeling age, sex and education as fixed effects and intercept and slope as random effects. For initial screen, we extracted individual residual cognitive slope estimates from the models and fit a linear regression model for each single nucleotide polymorphism (SNP), adjusting for population stratification. Results were meta-analyzed across cohorts. SNPs with p< 5x10 -8 were considered genome-wide significant and p < 5x10 -5 were considered suggestive. Results: A total of 3534 subjects were included. The average age at enrollment in each study ranged from 72 to 81, follow-up ranged from 2-18 years and incidence of clinical diagnosis of AD ranged from 19% to 34%. The most significant loci for decline in both global cognition and episodic memory was APOE (p¼3.1x10 -34 and p¼2.1x10 -24, respectively). Although no other non- APOE locus reached genome-wide significance, we found highly suggestive results at two other regions. First, for global cognition, near the EDAR gene with the top locus reaching a p¼8.9x10 -8 and second, on the RAB3GAP2 gene with the top locus reaching a p¼1.3x10 -7. Results were similar for episodic memory. We are currently analyzing data from two other cohort studies for validation. Top hits will be further investigated with full mixed effects models for all SNPs with p < 5x10 -4. Conclusions: Our findings to date suggest that cognitive decline may be a useful phenotype for identifying genomic variation associated with AD or other factors influencing cognitive decline.
P3-029
EXOME SEQUENCING IN A NOVEL FAMILIAL NEURONAL INTERMEDIATE FILAMENT INCLUSION DISEASE WITH UNKNOWN GENETIC DEFECT
Wan Zheng Chiu1, Tsz Hang Wong1, Guido Breedveld1, Annemieke Verkerk1, Ka Wan Li2, David Hondius2, Wouter Kamphorst3, John van Swieten4, 1Erasmus Medical Centre, Rotterdam, Netherlands; 2 Vrije Universiteit Medical Center, Amsterdam, Netherlands; 3VU University Medical Center, Amsterdam, Netherlands; 4Erasmus University Medical Center, Rotterdam, Netherlands. Contact e-mail: t.h.wong@ erasmusmc.nl Background: Neuronal intermediate filament inclusion disease (NIFID) is an uncommon neurodegenerative disorder characterised by early onset frontotemporal dementia with pyramidal and extrapyramidal signs. Neuropathologically, neuronal loss and gliosis are found and a-internexium and FUS have been found to be major components of the neuronal inclusions of NIFID. Here, we report a family with a-internexin positive, but FUS-negative neuronal inclusions, and aimed to identify the disease causing gene by performing exome sequencing. Methods: We report a Dutch family with fifteen affected members in seven generations. Three cases underwent pathological examination. We screened GAN and INA genes for mutations in one of these cases by direct sequencing. Exome sequencing and linkage analysis were performed in three pathologically confirmed cases and two cases with clinical diagnosis in this family. Results: We found no mutation in the GAN and INA genes. In our exome sequencing data we found 4854 mutations in at least one of the five patients by focusing on nonsynonymous variants, stopcodons, splice sites, frameshift indels and filtering against the public databases (dbSnp129, 1000 Genome and Exome Sequening Project 6500).Of these variants, 383 were found in the linkage regions. This results in 95 variants which are shared by 3 or more patients. Further filtering and prioritizing is still in process. Conclusions: We present for the first time a familial NIFID with primary a -internexin, but FUS-negative pathology. Results of exome sequencing should determine the disease causing gene in this neurodegenerative disease.
P3-030
EXCEPTIONAL COGNITIVE ABILITIES IN THE LONG LIFE FAMILY STUDY (LLFS)
Sandra Barral1, Stephanie Cosentino2, Rosann Costa3, Kaare Christensen4, John H. Eckfeldt5, Anne Newman6, Thomas Perls7, Michael A. Province8, Evan C. Hadley9, Winifred K. Rossi9, Richard Mayeux10, 1Columbia University Medical Center, New York, New York, United States; 2Columbia University Medical Center, New York, New York, United States; 3Columbia University Medical Center, New York, New York, United States; 4University of Southern Denmark, Odense, Denmark; 5University of Minnesota, Minneapolis, Minnesota, United States; 6University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States; 7Boston University, Boston, Massachusetts, United States; 8Washington University School of Medicine, St. Louis, Missouri, United States; 9National Institute on Aging, Bethesda, Maryland, United States; 10Columbia University, New York, New York, United States. Contact e-mail: [email protected] Background: The characterization of factors underlying inter-individual differences in cognitive performance is a well-researched topic. However, little is known about genetic influences on exceptional cognitive performance. We aim to define an exceptional memory phenotype (EM) and investigate whether there is a familial aggregation of EM within the Long Life Family Study (LLFS), a cohort of families selected for exceptional survival phenotypes. Methods: Using a sample of 1911 non-demented offspring of LLFS’s probands, we created a quantitative trait phenotype to identify subjects in LLFS offspring generation (N¼2552) with episodic memory scores 1.5 standard deviations above the mean, i.e., subjects with exceptional memory. We assessed differences in memory performance across the following four comparison groups using multivariate analysis adjusted for age, sex, education and APOE genotypes: i) LLFS’s offspring with exceptional memory (EM offspring) versus their unrelated spouses; ii) LLFS offspring without EM versus their unrelated spouses and iii) the parental generation of EM offspring versus the parental generation of LLFS’s offspring without exceptional memory (NEM offspring). Results: The frequency of EM phenotype among LLFS’s offspring was greater than its frequency among their spouses (21% versus 9.5%, respectively). The EM offspring demonstrated an exceptional performance on episodic memory compared to their unrelated spouses (b¼1.85, SE¼0.07, p< 0.001). Moreover, the parental generation of the EM offspring showed better performance on episodic memory when compared with the parental generation of NEM offspring (b¼0.81, SE¼0.20, p< 0.001). Finally, the spouses of EM offspring appeared to have higher episodic memory scores compared to the spouses of NEM offspring (b¼0.23, SE¼0.09, p¼0.031). None of the a nalyses found significant additional effects of APOE. Conclusions: We demonstrated that there is a familial correlation of an EM phenotype within LLFS cohort, suggesting that genetic polymorphisms might be influencing the exceptional performance of the offspring of long-lived individuals. P3-031
GENOME-WIDE ASSOCIATION STUDY IDENTIFIES SUSCEPTIBILITY LOCI ASSOCIATED WITH THE RATE OF COGNITIVE DECLINE
Jaeyoon Chung1, Richard Sherva1, Ryan Koesterer1, THE ALZHEIMER’S DISEASE GENETICS CONSORTIUM2, Jonathan Haines3, Margaret PericakVance4, Gerard Schellenberg5, Richard Mayeux6, Lindsay Farrer1, 1Boston University, Boston, Massachusetts, United States; 2University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 3 Vanderbilt University, Nashville, Tennessee, United States; 4University of Miami, Miami, Florida, United States; 5University of Pennsylvania, Philadelphia, Pennsylvania, United States; 6Columbia University, New York, New York, United States. Contact e-mail: [email protected] Background: We performed secondary analyses using a genome-wide association study dataset in order to identify genetic factors associated with cognitive decline. Methods: The sample included 771 Caucasian participants from the Washington Heights-Inwood Columbia Aging Study who were cognitively healthy or had mild cognitive impairment or Alzheimer disease (AD). Individuals were tested using 20 different cognitive
THE EFFECTS OF COGNITIVE RESERVE AND APOLIPOPROTEIN E ON HEALTHY COGNITIVE FUNCTION
David Ward1, Mathew Summers2, Nichole Saunders3, Michael Valenzuela4, Jeffery Summers5, Karen Ritchie6, Andrew Robinson7, James Vickers8, 1University of Tasmania/School of Medicine, Hobart/Tasmania, Australia; 2University of Tasmania/School of Psychology, Launceston, Tasmania, Australia; 3University of Tasmania, Hobart, Tasmania, Australia; 4University of Sydney/Sydney Medical School, Sydney, Australia; 5University of Tasmania/School of Psychology, Hobart, Australia; 6INSERM, Montpellier, France; 7University of Tasmania/School of Nursing and Midwifery, Hobart, Tasmania, Australia; 8University of Tasmania/School of Medicine, Hobart, Australia. Contact e-mail: David. [email protected] Background: Alzheimer’s disease research has identified environmental factors that delay the onset of dementia symptoms in the presence of disease processes. The beneficial effects of education, occupational status, and cognitively stimulating lifestyle activities are described through the theory of cognitive reserve, which are the individual differences in the efficient use and differential recruitment of brain networks due to life experience. Normally applied to pathological ageing, cognitive reserve has also been used to predict cognitive function in the face of normal age-related cognitive ageing, with mixed results. Similarly, apolipoprotein E is a genetic risk factor for late-onset Alzheimer’s disease that has shown mixed results when related to non-pathological cognitive function. The Tasmanian Healthy Brain Project is a prospective longitudinal study investigating such effects. Methods: Baseline data has been used to develop a cognitive reserve composite from a factor analysis of measures shown to modify dementia risk, investigate the relationship between ApoE allele status and cognitive reserve, and examine whether ApoE allele status and cognitive reserve interacted to predict non-pathological cognitive function. The study comprised 242 community-residing subjects (M age ¼ 61.20; SD ¼ 6.52) who undertook comprehensive neuropsychological examinations and genetic analysis. Results: Gel electrophoresis revealed an allelic distribution of 64.5% ε4 non-carrier and 35.5% ε4 carrier. Years of education, WAIS-III Full-scale IQ, and Lifetime of Experience scores were entered into principal components analysis that yielded a single significant cognitive reserve factor (eigenvalue ¼ 1.69) that explained 56.17% of the variance in the variables. Cognitive reserve factor z-scores were generated for subjects, with no significant difference in scores between ApoE ε4 carriers (M ¼ -.05; SD ¼ .94) and non-carriers (M ¼ .03; SD ¼ 1.03). Regression analysis showed cognitive reserve significantly predicted verbal memory performance in RAVLT total recall (r ¼ .17; p ¼ .03), Logical Memory delayed recall (r
P559
¼ .28; p < .01), and Letter Number Sequencing (r ¼ .22; p > .01) in ε4 non-carriers, whereas ε4 carriers did not possess such relationships. Conclusions: The results of this study demonstrated that cognitive reserve predicts ageing-susceptible verbal memory performance, but that the presence of this relationship was dependent on ε4 allele status. P3-027
OVEREXPRESSING HUMAN WILD- LRRK2 INCREASES SPATIAL RECOGNITION AND WORKING MEMORY PERFORMANCE IN MICE
Jun Ming Wang1, Samuel Adeosun2, Xu Hou2, Baoying Zheng2, University of Mississippi Medical Center, Jackson, Mississippi, United States; 2The University of Mississippi Medical Center, Jackson, Mississippi, United States. Contact e-mail: [email protected] 1
Background: The biological function of leucine-rich repeat kinase 2 (LRRK2), implicated in idiopathic Parkinson’s disease, has hitherto been elusive. Among other cellular and molecular mechanisms of learning and memory including neurite extension, synaptic functions, neurotransmitter release, LRRK2 has also been shown to play a role in regulating adult hippocampal neurogenesis. Even though LRRK2 seems to negatively regulate these processes, the implication of these findings in learning and memory is yet to be demonstrated. Methods: We carried out Y-Maze spontaneous alternation (spatial working memory) and novel arm discrimination (spatial recognition memory) tests in 7 month old female mice over-expressing the human wild type LRRK2 (LRRK2-Tg) and in non-transgenic agematched (Non-Tg) controls. Results: Surprisingly, LRRK2-Tg mice performed better than the Non-Tg mice in both tests. Exploration and locomotion were not different between the LRRK2-Tg and the Non-Tg mice. Conclusions: Despite its previously reported negative effects on neurite extension, synaptic functions, neurotransmitter release and neurogenesis, our currentresults suggest that LRRK2 modulate positively spatial memory behavior in mice. P3-028
GENOME-WIDE ASSOCIATION STUDY FOR COGNITIVE DECLINE
Lori Chibnik1, Lei Yu2, Towfique Raj3, Jishu Xu4, Nikolaos Patsopoulos4, Brendan Keenan5, Richard Sherva6, Sue Leurgans2, Deborah Blacker7, Robert Wilson8, Eric Reiman9, Matthew Huentelman10, The Alzheimer’s Disease Genetics Consortium11, Robert Green12, Lindsay Farrer6, Paul Crane13, David Weir14, Richard Mayeux15, Richard Lipton16, Gerard Schellenberg17, Denis Evans18, Philip De Jager1, David Bennett19, 1Brigham & Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States; 2Rush Alzheimer’s Disease Center, Chicago, Illinois, United States; 3Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts, United States; 4Brigham & Women’s Hospital, Boston, Massachusetts, United States; 5Brigham and Women’s Hospital, Boston, Massachusetts, United States; 6Boston University, Boston, Massachusetts, United States; 7Massachusetts General Hospital/Harvard Medical School, Harvard School of Public Health, Charlestown, Massachusetts, United States; 8Rush University Medical Center, Chicago, Massachusetts, United States; 9Banner Alzheimer’s Institute, Phoenix, Arizona, United States; 10TGen, Phoenix, Arizona, United States; 11University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 12Harvard Medical School, Boston, Massachusetts, United States; 13University of Washington School of Medicine, Seattle, Washington, United States; 14Institute for Social Research, Ann Arbor, Michigan, United States; 15Columbia University, New York, New York, United States; 16Albert Einstein College of Medicine, Bronx, New York, United States; 17University of Pennsylvania, Philadelphia, Pennsylvania, United States; 18Rush University Medical Center, Chicago, Illinois, United States; 19Rush University Medical Center, Chicago, Illinois, United States. Contact e-mail: [email protected]. harvard.edu Background: Cognitive decline, especially decline in episodic memory, is the clinical hallmark of Alzheimer’s disease (AD) and known to start long before the onset of clinically diagnosed AD dementia. Thus, it may serve
P560
Tuesday, July 16, 2013: Poster Presentations: P3
as a useful quantitative phenotype for GWAS and other "omics" analyses. Methods: We included non-Hispanic White participants from four prospective community-based cohort studies (ROS, MAP, CHAP, EAS) who were non-demented at study entry and have at least two repeated measures of cognition. Within each cohort, individual cognitive tests were combined to form aggregate measures of global cognition and episodic memory. Genotype data from each cohort was quality controlled and imputed using 1000Genomes reference panel. We used linear mixed effects models to characterize individual paths of change in cognition, modeling age, sex and education as fixed effects and intercept and slope as random effects. For initial screen, we extracted individual residual cognitive slope estimates from the models and fit a linear regression model for each single nucleotide polymorphism (SNP), adjusting for population stratification. Results were meta-analyzed across cohorts. SNPs with p< 5x10 -8 were considered genome-wide significant and p < 5x10 -5 were considered suggestive. Results: A total of 3534 subjects were included. The average age at enrollment in each study ranged from 72 to 81, follow-up ranged from 2-18 years and incidence of clinical diagnosis of AD ranged from 19% to 34%. The most significant loci for decline in both global cognition and episodic memory was APOE (p¼3.1x10 -34 and p¼2.1x10 -24, respectively). Although no other non- APOE locus reached genome-wide significance, we found highly suggestive results at two other regions. First, for global cognition, near the EDAR gene with the top locus reaching a p¼8.9x10 -8 and second, on the RAB3GAP2 gene with the top locus reaching a p¼1.3x10 -7. Results were similar for episodic memory. We are currently analyzing data from two other cohort studies for validation. Top hits will be further investigated with full mixed effects models for all SNPs with p < 5x10 -4. Conclusions: Our findings to date suggest that cognitive decline may be a useful phenotype for identifying genomic variation associated with AD or other factors influencing cognitive decline.
P3-029
EXOME SEQUENCING IN A NOVEL FAMILIAL NEURONAL INTERMEDIATE FILAMENT INCLUSION DISEASE WITH UNKNOWN GENETIC DEFECT
Wan Zheng Chiu1, Tsz Hang Wong1, Guido Breedveld1, Annemieke Verkerk1, Ka Wan Li2, David Hondius2, Wouter Kamphorst3, John van Swieten4, 1Erasmus Medical Centre, Rotterdam, Netherlands; 2 Vrije Universiteit Medical Center, Amsterdam, Netherlands; 3VU University Medical Center, Amsterdam, Netherlands; 4Erasmus University Medical Center, Rotterdam, Netherlands. Contact e-mail: t.h.wong@ erasmusmc.nl Background: Neuronal intermediate filament inclusion disease (NIFID) is an uncommon neurodegenerative disorder characterised by early onset frontotemporal dementia with pyramidal and extrapyramidal signs. Neuropathologically, neuronal loss and gliosis are found and a-internexium and FUS have been found to be major components of the neuronal inclusions of NIFID. Here, we report a family with a-internexin positive, but FUS-negative neuronal inclusions, and aimed to identify the disease causing gene by performing exome sequencing. Methods: We report a Dutch family with fifteen affected members in seven generations. Three cases underwent pathological examination. We screened GAN and INA genes for mutations in one of these cases by direct sequencing. Exome sequencing and linkage analysis were performed in three pathologically confirmed cases and two cases with clinical diagnosis in this family. Results: We found no mutation in the GAN and INA genes. In our exome sequencing data we found 4854 mutations in at least one of the five patients by focusing on nonsynonymous variants, stopcodons, splice sites, frameshift indels and filtering against the public databases (dbSnp129, 1000 Genome and Exome Sequening Project 6500).Of these variants, 383 were found in the linkage regions. This results in 95 variants which are shared by 3 or more patients. Further filtering and prioritizing is still in process. Conclusions: We present for the first time a familial NIFID with primary a -internexin, but FUS-negative pathology. Results of exome sequencing should determine the disease causing gene in this neurodegenerative disease.
P3-030
EXCEPTIONAL COGNITIVE ABILITIES IN THE LONG LIFE FAMILY STUDY (LLFS)
Sandra Barral1, Stephanie Cosentino2, Rosann Costa3, Kaare Christensen4, John H. Eckfeldt5, Anne Newman6, Thomas Perls7, Michael A. Province8, Evan C. Hadley9, Winifred K. Rossi9, Richard Mayeux10, 1Columbia University Medical Center, New York, New York, United States; 2Columbia University Medical Center, New York, New York, United States; 3Columbia University Medical Center, New York, New York, United States; 4University of Southern Denmark, Odense, Denmark; 5University of Minnesota, Minneapolis, Minnesota, United States; 6University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States; 7Boston University, Boston, Massachusetts, United States; 8Washington University School of Medicine, St. Louis, Missouri, United States; 9National Institute on Aging, Bethesda, Maryland, United States; 10Columbia University, New York, New York, United States. Contact e-mail: [email protected] Background: The characterization of factors underlying inter-individual differences in cognitive performance is a well-researched topic. However, little is known about genetic influences on exceptional cognitive performance. We aim to define an exceptional memory phenotype (EM) and investigate whether there is a familial aggregation of EM within the Long Life Family Study (LLFS), a cohort of families selected for exceptional survival phenotypes. Methods: Using a sample of 1911 non-demented offspring of LLFS’s probands, we created a quantitative trait phenotype to identify subjects in LLFS offspring generation (N¼2552) with episodic memory scores 1.5 standard deviations above the mean, i.e., subjects with exceptional memory. We assessed differences in memory performance across the following four comparison groups using multivariate analysis adjusted for age, sex, education and APOE genotypes: i) LLFS’s offspring with exceptional memory (EM offspring) versus their unrelated spouses; ii) LLFS offspring without EM versus their unrelated spouses and iii) the parental generation of EM offspring versus the parental generation of LLFS’s offspring without exceptional memory (NEM offspring). Results: The frequency of EM phenotype among LLFS’s offspring was greater than its frequency among their spouses (21% versus 9.5%, respectively). The EM offspring demonstrated an exceptional performance on episodic memory compared to their unrelated spouses (b¼1.85, SE¼0.07, p< 0.001). Moreover, the parental generation of the EM offspring showed better performance on episodic memory when compared with the parental generation of NEM offspring (b¼0.81, SE¼0.20, p< 0.001). Finally, the spouses of EM offspring appeared to have higher episodic memory scores compared to the spouses of NEM offspring (b¼0.23, SE¼0.09, p¼0.031). None of the a nalyses found significant additional effects of APOE. Conclusions: We demonstrated that there is a familial correlation of an EM phenotype within LLFS cohort, suggesting that genetic polymorphisms might be influencing the exceptional performance of the offspring of long-lived individuals. P3-031
GENOME-WIDE ASSOCIATION STUDY IDENTIFIES SUSCEPTIBILITY LOCI ASSOCIATED WITH THE RATE OF COGNITIVE DECLINE
Jaeyoon Chung1, Richard Sherva1, Ryan Koesterer1, THE ALZHEIMER’S DISEASE GENETICS CONSORTIUM2, Jonathan Haines3, Margaret PericakVance4, Gerard Schellenberg5, Richard Mayeux6, Lindsay Farrer1, 1Boston University, Boston, Massachusetts, United States; 2University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 3 Vanderbilt University, Nashville, Tennessee, United States; 4University of Miami, Miami, Florida, United States; 5University of Pennsylvania, Philadelphia, Pennsylvania, United States; 6Columbia University, New York, New York, United States. Contact e-mail: [email protected] Background: We performed secondary analyses using a genome-wide association study dataset in order to identify genetic factors associated with cognitive decline. Methods: The sample included 771 Caucasian participants from the Washington Heights-Inwood Columbia Aging Study who were cognitively healthy or had mild cognitive impairment or Alzheimer disease (AD). Individuals were tested using 20 different cognitive