- Email: [email protected]
The genetic basis of episodic memory performance in the elderly: Is there a link to micro-RNAs?
P558
Tuesday, July 16, 2013: Poster Presentations: P3
3 F. Hoffmann-La Roche AG, Basel, Switzerland. Contact e-mail: annica. [email protected]
Background: A number of mutations in the gene encoding microtubule associated protein tau, MAPT, are located in exon 10 or in the flanking intronic regions. These mutations have been shown to affect alternative splicing of exon 10, resulting in increased production of tau protein containing four repeats of the microtubule binding domains. Here we describe a novel variation upstream of exon 10 in a patient clinically diagnosed with frontotemporal dementia with a positive family history of dementia. Methods: MAPT mutation analysis was performed by direct sequencing of exons 1, 9-13 and the flanking intronic regions. Neuropathological analysis was performed using routine histopathological methods and immunohistochemical analysis was performed with antibodies recognizing different phospho-epitopes in the tau protein on formalin-fixed paraffin embedded sections. Results: Sequencing of the MAPT gene revealed a silent mutation in the coding region (P207P), previously reported to be non-pathogenic. In addition we identified a previously unknown variation in intron 9 (IVS9-11G>C), located in the polypyrimidine tract upstream of exon 10. The neuropathological assessment demonstrated neuronal loss which was most evident in frontal and temporal cortices, hippocampus and substantia nigra. Abundant phospho-tau immunopositive neuronal cytoplasmic inclusions and oligodendroglial coiled bodies were found. Conclusions: The novel variation in intron 9 of MAPT is located in the polypyrimidine tract upstream of exon 10, which previously have been suggested to affect the splicing of exon 10. Further studies are needed to determine whether the IVS9-11G>C variation is pathogenic, but the current literature suggests that this variation might affect splicing of MAPT resulting in an increase in four-repeat tau isoforms.
P3-023
GENETIC ANALYSIS OF PGRN AND MAPT GENES IN KOREANS WITH DIVERSE NEURODEGENERATIVE DISORDERS
Eva Bagyinszky1, Young Ho Park2, Jae-Won Jang3, Lingyan Shen4, Young Chul Youn5, Seong An6, SangYun Kim7, 1Gachon University BioNano Department, Seongnam-si, South Korea; 2Department of Neurology, Seoul National University Bundang Hospital, Seongnam-si, South Korea; 3Seoul National University Bundang Hospital, Sungnam, South Korea; 4Gachon University Department of BioNano Technology, Seongnam-si, South Korea; 5Dept. of Neurology, College of Medicine, Chung-Ang University, Seoul, South Korea; 6Gachon University, Sungnam-si, South Korea; 7Department of Neurology, Seoul National University Budang Hospital, Gyeonggi-do, Korea, Seongnam-si, South Korea. Contact e-mail: [email protected] Background: After Alzheimer’s disease (AD), frontotemporal Dementia (FTD) is the second most common form of neurodegenerative dementia. Progranulin (PGRN) and Microtubule-associated Tau protein (MAPT) genes are the major risk factor genes for FTD. Since the differential diagnosis of the neurodegenerative disorders is still problematic, potential mutations in PGRN and MAPT genes were screened. Methods: In our project, PCR-based genetic analysis was performed with PGRN exon 1-5 and 8-12 and MAPT exon 1 and 8-12. After PCR, single strand conformation polymorphism (SSCP) analysiswas carried out for detecting polymorphisms. The samples with different electrophoretic patternswere selected for sequencing. Results: Different SSCP mobilities were detected in PGRN exon 2-3 from 8 out of 27patients. Intronic polymorphism (rs9897526) was detected at the PGRN intron3. Further findings will be presented the AAIC 2013. Conclusions: PGRN rs9897526 is a common polymorphism. European studies suggested that it might reduce the age of onset of amyotrophic lateral sclerosis (ALS) or AD. The differential diagnosis of the neurodegenerative dementias is challenging, especially in the early stages of the disease. FTD might be easily misdiagnosed to AD. Genetic testing of other risk factor genes in various dementia, FTD, ALS, Parkinson’s Disease (PD), vascular dementia (VD) and Creutzfeldt-Jakob Disease (CJD), should be important for accurate diagnosis of specific dementia.
P3-024
GENETIC MODIFIERS OF COGNITIVE MAINTENANCE
Jennifer Yokoyama1, Daniel Evans2, Carrie Nielson3, Gregory Tranah2, Kristine Yaffe4, 1University of California, San Francisco, San Francisco, California, United States; 2CPMC Research Institute, San Francisco, California, United States; 3OHSU Public Health & Preventive Medicine, Portland, Oregon, United States; 4University of California San Francisco, San Francisco, California, United States. Contact e-mail: jyokoyama@ memory.ucsf.edu Background: Much attention has focused on cognitive impairment associated with aging, yet a significant proportion of older adults maintain high levels of cognitive function. Identification of genetic factors associated with cognitive maintenance in elderly populations could provide critical insight into the brain’s ability to cope with biological changes that occur with the aging process. Methods: We undertook a genome-wide association study (GWAS) of approximately 2.4 million single nucleotide polymorphisms (SNPs) to identify modifiers of cognitive trajectories in two population-based cohorts of elderly Caucasian participants, the Study of Osteoporotic Fractures (SOF, 100% female, n¼3508, mean age¼71.961.2 years) and the Osteoporotic Fractures in Men Study (MrOS, 0% female, n¼3820, mean age¼75.261.2 years). Standardized measures of global cognitive function (z-scores) over 10 and 6 years were calculated among SOF and MrOS participants and mixed model regression was used to determine subject-specific cognitive slopes and intercepts. Fixed effects included clinical site, baseline age, and education. "Cognitive maintenance" was defined as a change in global cognitive function (slope) of 0. In addition, two other groups were created: "minor decliners" had cognitive slope <0 but within 1 SD from the mean, and "major decliners" had a slope <1 SD below the mean. The primary GWAS compared cognitive maintainers versus minor and major decliners. MrOS and SOF GWAS results were combined using fixed effect meta-analysis with inverse variance weights. Top association findings (P<0.01) were investigated for gene ontology pathway enrichment using WebGestalt. Results: The most significant SNP association with cognitive maintenance was rs7109806 (P¼7.8x10 -8), which was located between RIC3 and LMO1. RIC3 modulates activity of alpha7 nicotinic acetylcholine receptors (AChRs); alpha7 AChRs have been implicated in synaptic plasticity and may contribute to cognitive deficits in Alzheimer’s disease via their binding with beta-amyloid. LMO1 is a transcriptional regulator that was recently associated with neuroblastoma. Pathway analysis of top GWAS findings suggested enrichment of nervous system development genes in cognitive maintenance. Conclusions: These findings suggest that there may be genetic loci that promote healthy cognitive aging and that these loci may be involved in nervous system development. Future work is required to validate RIC3 and/ or LMO1 as candidate genes involved in cognitive maintenance. P3-025
THE GENETIC BASIS OF EPISODIC MEMORY PERFORMANCE IN THE ELDERLY: IS THERE A LINK TO MICRO-RNAS?
Julia Schr€oder1, Sara Ansaloni1, Marcel Schilling1, Tian Liu2, Goran Papenberg2, Ulman Lindenberger2, Shu-Chen Li2, Lars Bertram1, 1 Max Planck Institute for Molecular Genetics, Berlin, Germany; 2Max Planck Institute for Human Development, Berlin, Germany. Contact e-mail: [email protected] Background: Memory performance in humans is genetically controlled, and progressive memory decline is one of the earliest clinical symptoms in Alzheimer’s disease (AD). In this project, we explore the genetic basis of episodic memory performance with a particular focus on the potential dysfunction of microRNA (miRNA) related pathways. miRNAs are a class of non-coding RNAs involved in the post-transcriptional regulation of protein expression, including those involved in cognitive phenotypes. Methods: Memory performance was assessed in participants of the Berlin Aging Study II (BASE-II). Here, we first determined whether genetic loci established to affect risk for AD (see www.alzgene.org) are also correlated with episodic memory functions in the participants using genome-wide association study (GWAS) data. Second, we are currently performing GWAS
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
Tuesday, July 16, 2013: Poster Presentations: P3
3 F. Hoffmann-La Roche AG, Basel, Switzerland. Contact e-mail: annica. [email protected]
Background: A number of mutations in the gene encoding microtubule associated protein tau, MAPT, are located in exon 10 or in the flanking intronic regions. These mutations have been shown to affect alternative splicing of exon 10, resulting in increased production of tau protein containing four repeats of the microtubule binding domains. Here we describe a novel variation upstream of exon 10 in a patient clinically diagnosed with frontotemporal dementia with a positive family history of dementia. Methods: MAPT mutation analysis was performed by direct sequencing of exons 1, 9-13 and the flanking intronic regions. Neuropathological analysis was performed using routine histopathological methods and immunohistochemical analysis was performed with antibodies recognizing different phospho-epitopes in the tau protein on formalin-fixed paraffin embedded sections. Results: Sequencing of the MAPT gene revealed a silent mutation in the coding region (P207P), previously reported to be non-pathogenic. In addition we identified a previously unknown variation in intron 9 (IVS9-11G>C), located in the polypyrimidine tract upstream of exon 10. The neuropathological assessment demonstrated neuronal loss which was most evident in frontal and temporal cortices, hippocampus and substantia nigra. Abundant phospho-tau immunopositive neuronal cytoplasmic inclusions and oligodendroglial coiled bodies were found. Conclusions: The novel variation in intron 9 of MAPT is located in the polypyrimidine tract upstream of exon 10, which previously have been suggested to affect the splicing of exon 10. Further studies are needed to determine whether the IVS9-11G>C variation is pathogenic, but the current literature suggests that this variation might affect splicing of MAPT resulting in an increase in four-repeat tau isoforms.
P3-023
GENETIC ANALYSIS OF PGRN AND MAPT GENES IN KOREANS WITH DIVERSE NEURODEGENERATIVE DISORDERS
Eva Bagyinszky1, Young Ho Park2, Jae-Won Jang3, Lingyan Shen4, Young Chul Youn5, Seong An6, SangYun Kim7, 1Gachon University BioNano Department, Seongnam-si, South Korea; 2Department of Neurology, Seoul National University Bundang Hospital, Seongnam-si, South Korea; 3Seoul National University Bundang Hospital, Sungnam, South Korea; 4Gachon University Department of BioNano Technology, Seongnam-si, South Korea; 5Dept. of Neurology, College of Medicine, Chung-Ang University, Seoul, South Korea; 6Gachon University, Sungnam-si, South Korea; 7Department of Neurology, Seoul National University Budang Hospital, Gyeonggi-do, Korea, Seongnam-si, South Korea. Contact e-mail: [email protected] Background: After Alzheimer’s disease (AD), frontotemporal Dementia (FTD) is the second most common form of neurodegenerative dementia. Progranulin (PGRN) and Microtubule-associated Tau protein (MAPT) genes are the major risk factor genes for FTD. Since the differential diagnosis of the neurodegenerative disorders is still problematic, potential mutations in PGRN and MAPT genes were screened. Methods: In our project, PCR-based genetic analysis was performed with PGRN exon 1-5 and 8-12 and MAPT exon 1 and 8-12. After PCR, single strand conformation polymorphism (SSCP) analysiswas carried out for detecting polymorphisms. The samples with different electrophoretic patternswere selected for sequencing. Results: Different SSCP mobilities were detected in PGRN exon 2-3 from 8 out of 27patients. Intronic polymorphism (rs9897526) was detected at the PGRN intron3. Further findings will be presented the AAIC 2013. Conclusions: PGRN rs9897526 is a common polymorphism. European studies suggested that it might reduce the age of onset of amyotrophic lateral sclerosis (ALS) or AD. The differential diagnosis of the neurodegenerative dementias is challenging, especially in the early stages of the disease. FTD might be easily misdiagnosed to AD. Genetic testing of other risk factor genes in various dementia, FTD, ALS, Parkinson’s Disease (PD), vascular dementia (VD) and Creutzfeldt-Jakob Disease (CJD), should be important for accurate diagnosis of specific dementia.
P3-024
GENETIC MODIFIERS OF COGNITIVE MAINTENANCE
Jennifer Yokoyama1, Daniel Evans2, Carrie Nielson3, Gregory Tranah2, Kristine Yaffe4, 1University of California, San Francisco, San Francisco, California, United States; 2CPMC Research Institute, San Francisco, California, United States; 3OHSU Public Health & Preventive Medicine, Portland, Oregon, United States; 4University of California San Francisco, San Francisco, California, United States. Contact e-mail: jyokoyama@ memory.ucsf.edu Background: Much attention has focused on cognitive impairment associated with aging, yet a significant proportion of older adults maintain high levels of cognitive function. Identification of genetic factors associated with cognitive maintenance in elderly populations could provide critical insight into the brain’s ability to cope with biological changes that occur with the aging process. Methods: We undertook a genome-wide association study (GWAS) of approximately 2.4 million single nucleotide polymorphisms (SNPs) to identify modifiers of cognitive trajectories in two population-based cohorts of elderly Caucasian participants, the Study of Osteoporotic Fractures (SOF, 100% female, n¼3508, mean age¼71.961.2 years) and the Osteoporotic Fractures in Men Study (MrOS, 0% female, n¼3820, mean age¼75.261.2 years). Standardized measures of global cognitive function (z-scores) over 10 and 6 years were calculated among SOF and MrOS participants and mixed model regression was used to determine subject-specific cognitive slopes and intercepts. Fixed effects included clinical site, baseline age, and education. "Cognitive maintenance" was defined as a change in global cognitive function (slope) of 0. In addition, two other groups were created: "minor decliners" had cognitive slope <0 but within 1 SD from the mean, and "major decliners" had a slope <1 SD below the mean. The primary GWAS compared cognitive maintainers versus minor and major decliners. MrOS and SOF GWAS results were combined using fixed effect meta-analysis with inverse variance weights. Top association findings (P<0.01) were investigated for gene ontology pathway enrichment using WebGestalt. Results: The most significant SNP association with cognitive maintenance was rs7109806 (P¼7.8x10 -8), which was located between RIC3 and LMO1. RIC3 modulates activity of alpha7 nicotinic acetylcholine receptors (AChRs); alpha7 AChRs have been implicated in synaptic plasticity and may contribute to cognitive deficits in Alzheimer’s disease via their binding with beta-amyloid. LMO1 is a transcriptional regulator that was recently associated with neuroblastoma. Pathway analysis of top GWAS findings suggested enrichment of nervous system development genes in cognitive maintenance. Conclusions: These findings suggest that there may be genetic loci that promote healthy cognitive aging and that these loci may be involved in nervous system development. Future work is required to validate RIC3 and/ or LMO1 as candidate genes involved in cognitive maintenance. P3-025
THE GENETIC BASIS OF EPISODIC MEMORY PERFORMANCE IN THE ELDERLY: IS THERE A LINK TO MICRO-RNAS?
Julia Schr€oder1, Sara Ansaloni1, Marcel Schilling1, Tian Liu2, Goran Papenberg2, Ulman Lindenberger2, Shu-Chen Li2, Lars Bertram1, 1 Max Planck Institute for Molecular Genetics, Berlin, Germany; 2Max Planck Institute for Human Development, Berlin, Germany. Contact e-mail: [email protected] Background: Memory performance in humans is genetically controlled, and progressive memory decline is one of the earliest clinical symptoms in Alzheimer’s disease (AD). In this project, we explore the genetic basis of episodic memory performance with a particular focus on the potential dysfunction of microRNA (miRNA) related pathways. miRNAs are a class of non-coding RNAs involved in the post-transcriptional regulation of protein expression, including those involved in cognitive phenotypes. Methods: Memory performance was assessed in participants of the Berlin Aging Study II (BASE-II). Here, we first determined whether genetic loci established to affect risk for AD (see www.alzgene.org) are also correlated with episodic memory functions in the participants using genome-wide association study (GWAS) data. Second, we are currently performing GWAS
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