Primary Prevention of Dementia: Research Findings from the Singapore Longitudinal Ageing Studies

1. 24th International Conference of Alzheimer’s Disease International (ADI 2009), March 25th – 28th 2009, Singapore. ‘Dementia: Engaging Societies Around the World’. Parallel Session: ‘Dementia Care and Research in Asian Countries’ Primary Prevention of Dementia: Research Findings from the Singapore Longitudinal Ageing Studies Tze Pin Ng Principal Investigator and Coordinator Gerontological Research Programme, Singapore Supported by grants from Biomedical Research Council (03/1/21/17/214)

2. Singapore Multi-Ethnic Population: 3 million Chinese 77% Malay 14% Indian 7% Aged 65+ 8% in 2003 18% in 2030

3. Percent Increase in Elderly Population: 2000 to 2030 Singapore Philippines South Korea India Canada United States United Kingdom Source: U.S. Census Bureau, 2000a

4. National Mental Health Survey 2003 • Cross-sectional survey of a national random sample of older adults aged 60+ • 1,092 participants (72.4% response) • Multi-ethnic and multi-language team of trained field interviewers interviewed respondents in their homes • Mental disorders were diagnosed using Geriatric Mental State (GMS)

5. Singapore Longitudinal Aging Studies • Population-based observational propsective cohort study of older adults aged 55+ in South East Singapore • 2,804 participants (78.5% response) • Baseline data on a wide range of demographic, biological, clinical, psychosocial and behavioral characteristics • Extensive battery of structured health interviews, assessments and blood tests. • Follow up assessment after 2 years and 4 years.

8. Dementia Prevalence in Singapore

10. Risk and Primary Prevention Factors • Age, Gender, Ethnicity • Education • Blood pressure • Depression • Physical, social and productive activities • Nutrition: Anti-Oxidants and Micronutrients • APOE-e4 gene interaction

11. Cognitive Performance: Demographic Factors Significant correlates of MMSE Ng TP, Niti M, Chiam PC, Kua EH. Ethnic And Educational Differences In Cognitive Test Performance On Mini-Mental State Examination In Asians. American Journal of Geriatric Psychiatry 2007. Feb;15(2):130-9.

12. Adjusted# Mean MMSE Scores: Ethnic Differences by Educational Groups # adjusted for age, gender, education, vascular risk factors and diseases, other comorbidities, SF-12 PCS & MCS, ADL–IADL and leisure time activities NS NS †** ‡*** ‡** †*** * p<0.05 ** p<0.01 *** p<0.001 ns=not significant at p<0.05 † Chinese versus Malay ‡ Chinese versus Indians § Indians versus Malays

13. Blood pressure and cognitive decline (12%) (25%) (18%) (25%) (16%) (4%) Low BP Normal BP High BP Under-treated Well-treated Over-treated Undiagnosed Untreated Hypertension Diagnosed and Treated Unpublished data from the Singapore Longitudinal Aging Studies

14. Blood pressure instability Cognitive impairment (MMSE≤23) in participants free of cardiovascular disease and stroke (N=2,294) Percent OR=4.10 (P=0.03) OR=1.15 (P=0.67) OR=0.48 (P=0.02) Yap P, Niti M, Yap KB, Ng TP. Orthostatic hypotension, hypotension and cognitive status: early co-morbid markers of primary dementia? Dement Geriatr Cogn Disord 2008;26:239–246

15. Mean MMSE Scores By Chronic Medical Illnesses Adjusted for Age, Education, Gender and Ethnicity N.S. N.S. N.S. P=0.012 P<0.001 P<0.001 P<0.001

16. Depressive symptoms and incident cognitive impairment in men, not women % with Incident Cognitive impairment P=0.03 Interaction p=0.02 P=0.71 Women Men Unpublished results from SLAS

17. Association of depression with cognitive decline is modified by APOE-e4 status % with cognitive decline P=0.04 Interaction p=0.03 P=0.22 Non-APOE-e4 carriers APOE-e4 carriers Niti M, Yap KB, Kua EH, Ng TP. APOE ε4, depressive symptoms and cognitive decline in Chinese older adults: Singapore Longitudinal Aging Studies Journal of Gerontology Series A Medical Sciences (In press)

18. Physical, mental and social activities

19. Leisure Time Activities

20. Leisure activities and cognitive decline Relative Risk of Cognitive Decline Low Moderate High Level of Leisure Time Activities Niti M, Yap KB, Kua EH, Tan CH, Ng TP. Physical, social and productive leisure activities, cognitive decline and interaction with APOE-epsilon4 genotype in Chinese older adults. Int Psychogeriatrics. 2008 Jan 11;:1-15

21. Physical vs Social vs Productive activities Odds Ratio Niti M, Yap KB, Kua EH, Tan CH, Ng TP. Physical, social and productive leisure activities, cognitive decline and interaction with APOE-epsilon4 genotype in Chinese older adults. Int Psychogeriatrics. 2008 Jan 11;:1-15

22. APOE-e4 modifies the effect of leisure time activities on cognitive decline

23. Nutritional deficiencies in elderly • More than a third of elderly in the community are at risk of malnutrition • Factors: • chronic diseases • multiple drugs use • reduced mobility • age-related physiological and social changes. • Marginal or biochemical (‘subclinical’) deficiencies may have significant health effects

24. General Nutritional Status and Cognitive Health Relative Risks of Cognitive Impairment Ng TP, Feng L, Niti M,Yap KB. Albumin, Hemoglobin, Low Body Mass and Cognitive Impairment in Community-Dwelling Chinese Older Adults. Age Ageing. 2008 May 20. [Epub ahead of print]

25. Micronutrients and phytochemicals: ‘brain’ food? Neuroprotective, anti-oxidant, anti-inflammatory properties • Folate, B12 • Fish oil and Omega-3 Poly-Unsaturated Fatty Acids (PUFA) • Tea polyphenols • Curcumins

26. Current state of knowledge • Experimental evidence support biological actions and effects • Human evidence of effectiveness are limited • Few randomized controlled trials have provided conclusive evidence to support the safe use of nutritional supplements for preventing or slowing dementia.

27. Folate, B12 and Homocysteine

28. Folate, B12 and Homocysteine and CNS Function • Folate provides the methyl group for the conversion of methionine to S-adenosylmethionine (SAM) • SAM is the major methyl donor for most methyltransferase reactions • Folate deficiency and B12 cause reduced synthesis of methionine and SAM (hypomethylation). • Build up of homocysteine: Damage the brain through vascular mechanism and as a neurotoxin.

29. Neuropsychological Tests

30. Folate Elevated Folate is associated with better memory and learning and language ability Cognitive scores change per SD increase of folate in blood Feng L, Ng TP, Chuah L, Niti M, Kua EH. Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study. Am J Clin Nutr. 2006 Dec;84(6):1506-12.

31. Homosysteine Elevated homocysteine is associated with deficits in processing speed and constructional ability Cognitive scores change per unit increase of homocysteine NS NS NS p=0.021 p=0.010 Feng L, Ng TP, Chuah L, Niti M, Kua EH. Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study. Am J Clin Nutr. 2006 Dec;84(6):1506-12.

32. Feng L, Niti M, Yap KB, Kua EH, Ng TP. Vitamin B-12, Apolipoprotein E Genotype and Cognitive Performance: Evidence of Gene-Nutrition Interaction. Am J Clin Nutr (Accepted for publication)

33. Omega-3 fatty Acids

34. Omega-3 Biological Actions • DHA is a primary component of membrane phospholipids in the brain, essential for maintaining membrane integrity and neuronal function • DHA promotes neuronal membrane excitability, increase neurotransmitter levels and reduce neuronal damage • Reduce brain plaque formation from amyloid precursor protein and increasing its clearance. • Reduce cardiovascular disease and non-haemorrhagic stroke risk • Antiarrhythmic, antithrombotic, anti-inflammatory and antiatherogenic effects • Lower serum triglyceride levels, lower blood pressure and improved endothelial function • Reduce synthesis of pro-inflammatory cytokines, attenuate the pro-inflammatory process in AD

35. SLAS Subjects Relative Risk of Cognitive Decline Omega 3 supplements Unpublished data from Singapore Longitudinal Aging Studies

36. Turmeric and Curcumin • Indian yellow curry spice contains, as major constituent, turmeric • Turmeric is the dried rhizome of Curcuma longa, a member of the ginger family (Zingiberaceae). • Widely used among Asians as a food flavoring and preservative, • Traditionally used as a herbal remedy for the treatment of coryza, indigestion, gallstone and hepatic disorders and rheumatism, and to promote healing of cuts and wounds. • Curcumin (1,7-bis-(-4-hydroxy-3-methoxiphenyl)-1,6-heptadiene-2,5-dione) and curcuminoid products are isolated from turmeric.

37. Curcumin • Potent anti-inflammatory and anti-oxidant properties. • Inhibits in vitro lipid peroxidation, scavenges free oxygen and NO-based radicals • Anti-atherogenic effects • In human healthy subjects, the daily intake of 200 mg of curcumin lower total blood lipid peroxides as well as in HDL and LDL-lipid peroxidation, normalize plasma levels of fibrinogen and of apo B/apo A ratio. • In a Alzheimer transgenic mouse model, both low (160 ppm) and high doses of dietary curcumin (5000 ppm) significantly • lowered oxidized proteins and interleukin-1a • reduced insoluble and soluble β-amyloid and plaque burden.

38. Curry Intake and Cognition Cognitive (MMSE) Scores Ng, T P, PC Chiam, HC Chua, L Lim and E H Kua, Curry consumption and cognitive function in the elderly. Am J of Epidemiol 2006;164,9:898-906.

39. Tea catechins: experimental evidence of neuroprotective effects • Experimental and animal studies show that tea and tea polyphenols possess potent neuroprotective activity • Catechins, e.g. epigallocatechin-3-gallate (EGCG), evoke cellular mechanisms related to neuroprotective as well as neurorescue activities. • Protective effects against B-amyloid–induced neurotoxicity by enhancing the release of the non-amyloidogenic soluble form of amyloid precursor protein (APP). • EGCG and tea is protective against Parkinson’s disease in a mice model and one epidemiological study.

40. Japanese Study

41. Relative Risk of Cognitive Decline Tea Intake Ng TP, Feng L, Niti M, Kua EH, Yap KB. Tea Intake and Cognitive Impairment and Decline. Am J Clin Nutr. (2008 Jul;88(1):224-31

42. Further Studies • Singapore Longitudinal Ageing Studies • Primary prevention RCT of folate for cognitive functioning • Phase 2 and 3 trials of curcumins and turmeric

43. Thank You Questions and Answers