The effects of cognitive reserve and apolipoprotein E on healthy cognitive function

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

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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