FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PSYCHOLOGICAL MEDICINE NATIONAL UNIVERSITY OF SINGAPORE

LIPIDS AND COGNITION IN CHINESE OLDER ADULTS: INVESTIGATING APOE, PON1, N-3 PUFA IN THE SINGAPORE LONGITUDINAL AGING STUDIES GAO QI (BACHELOR OF CLINICAL MEDICINE; MASTER OF CLINICAL MEDICINE) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF PSYCHOLOGICAL MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2013 I ACKNOWLEDGEMENTS I am most grateful to my knowledgeable and dedicated supervisor, Professor Ng Tze Pin I wish to express my sincere appreciation for the kindness he has always shown towards me and for the excellent methods of his teaching which make PhD study a real pleasure I always remember what he said when I first met him on 22 July 2008: think big, dig deep, start small and act fast It would be impossible for me to complete this PhD thesis without his expertise, encouragements, and concrete helps I also would like to thank Dr Philip Yap and the staff at the Geriatric Clinic KTPH (previously known as the Memory Clinic Alexandra Hospital), for their input and contribution to my research work My thesis would not have been completed if not for their friendly and timely assistance I wish to express my sincere gratitude to Prof John Wong, the head of Department of Psychological Medicine I am deeply grateful for his strong support and encouragement for my thesis writing and submission I would like to give thanks to all the research staffs, research nurses, and the elderly participants of the Singapore Longitudinal Ageing Study (SLAS), the staffs in the Department of Psychological Medicine National University of Singapore, for all your helps, supports, and instructions in the past six years I would also like to thank to the National University of Singapore, for awarding me the Research Scholarship in the four-year candidature, thus supporting both my daily life and my thesis work I sincerely hope that I could contribute more to Singapore, a dynamic and promising country II Finally, I would express my endless thanks to my parents, my family members and my best friends in China, United States and Japan, for their unconditional love, heartening words and encouragements during my lonely and hard times Especially thanks to Chun-Wei, for helping make my dreams come true Thanks for the touching and beautiful moments It is the best thing that ever happened in my life III CONTENTS DECLARATION PAGE I ACKNOWLEDGEMENTS II SUMMARY VII LIST OF TABLES IX LIST OF FIGURES XI LIST OF ABBRIVIATIONS XII LIST OF APPENDICES XV INTRODUCTION 1.1 Aging population 1.2 Cognitive decline and dementia in the elderly 1.3 Risk and protective factors in cognitive decline and dementia 1.4 The role of lipids in elderly cognition 1.5 Objectives of the current study LITERATURE REVIEW 2.1 n-3 PUFAs and cognition in the elderly 2.1.1 Cardiovascular protective mechanisms of n-3 PUFAs 2.1.2 Neuroprotective mechanisms of n-3 PUFAs 2.1.3 Cross-sectional studies 2.1.4 Prospective cohort studies 10 2.1.5 Clinical Trials 12 2.2 APOE and cognition in the elderly 15 2.2.1 APOE gene polymorphism 16 IV 2.2.2 Neurobiological role of APOE 17 2.2.3 APOE and AD 18 2.2.4 APOE and VaD 20 2.3 PON1 gene 192 Q/R polymorphism and cognition in the elderly 21 2.3.1 PON1 and its biological activities 21 2.3.2 PON1 gene 192 Q/R polymorphism and dementia 22 METHODS 24 3.1 Study population 24 3.1.1 Community-based 24 3.1.2 Clinical-based 27 3.2 Study design and Sample size 28 3.2.1 Study I 28 3.2.2 Study II 28 3.2.3 Study III 29 3.2.4 Study IV 29 3.2.5 Study V 29 3.3 Outcome measurements 30 3.3.1 Cognitive performance 30 3.3.2 Clinical manifestations and disease severity of dementia 33 3.3.3 Omega-3 intake 34 3.3.4 APOE and PON1 genotyping 35 3.3.5 Covariates 37 3.4 Statistical analysis 38 3.4.1 Study I 38 3.4.2 Study II 39 V 3.4.3 Study III 39 3.4.4 Study IV 40 3.4.5 Study V 40 RESULTS AND DISCUSSION 41 4.1 Study I 41 4.1.1 Results 41 4.1.2 Discussion 44 4.2 Study II 47 4.2.1 Results 47 4.2.2 Discussion 56 4.3 Study III 61 4.3.1 Results 61 4.3.2 Discussion 66 4.4 Study IV 69 4.4.1 Results 69 4.4.2 Discussion 79 4.5 Study V 82 4.5.1 Results 82 4.5.2 Discussion 93 SUMMARY AND CONCLUSION 97 REFERENCES 101 LIST OF PUBLICATIONS 127 LIST OF CONFERENCE PRESENTATIONS 128 APPENDICES 129 VI SUMMARY Background: A number of lipids function as protective or risk factors in human cognition Published findings are inconsistent and/or insufficient Few data are available for Asian population Objective: To examine the relationship of APOE ε4, PON1 polymorphism and n-3 PUFA and cognition (cognitive performance, cognitive decline and dementia) in elderly Chinese Singaporeans Methods: The study subjects were recruited from two sources: (1) Chinese participants in the Singapore Longitudinal Ageing Study-1 (SLAS-1) and (2) Chinese patients with confirmed diagnosis of dementia from Alexandra Hospital Study I investigated the association of n-3 PUFA supplements intake with cognitive decline Study II investigated the association of n-3 PUFA supplements intake and cognitive performance Study III investigated the association of APOE ε4 allele and dementia Study IV investigated the PON1 gene 192Q/R polymorphism and its association with clinical manifestations and disease severity of dementia among patients with AD and mixed dementia Study V investigated the association between PON1 gene 192Q/R polymorphism and the risk of dementia and the interaction between APOE ε4 status and PON1 gene 192Q/R polymorphism Results: Study I found that daily n-3 PUFA supplements intake was significantly associated with lower risk of cognitive decline (adjusted OR=0.23, 95% C.I 0.07-0.75, P=0.015) Study II showed daily intake of n-3 PUFA supplements was independently associated with better cognitive performance on memory (β=0.098, SE=0.31, P=0.006), executive function (β=0.071, SE=0.43, P=0.046) and information processing speed (β=0.074, SE=0.24, P=0.036) Study III showed significant differences in the prevalence of APOE ε4 allele between AD patients and cognitively normal controls (35.6% and 17.2% respectively, P =0.005), Odds ratio (OR) of the association adjusted for education was 2.41, 95% C.I.1.10-5.28, P=0.028 No significant VII association of APOE ε4 allele with VaD/mixed dementia was found Study IV found that the PON1 R allele was significantly associated with more neuropsychiatric symptoms among dementia patients overall In the mixed dementia subgroup, the R allele was significantly associated with three fold increased NPI(S) scores (9.01 versus 3.11, P=0.039) and NPI (CD) scores (9.09 versus 2.33, P=0.006), CDR (sum of boxes) score (8.57 versus 5.89, P=0.042), GDS/FAST score (4.84 versus 4.11, P=0.007) and BADLS score (6.99 versus 1.00, P