Prevention of Alzheimer’s disease – is it possible?

1. Prevention of Alzheimer’s disease – is it possible? Miia Kivipelto, MD, PhDProfessor Karolinska Institutet Alzheimer Disease Research Center (KI-ADRC) and Karolinska University Hospital, Sweden

2. Prevention of cognitive impairment and Alzheimer’s disease • So far so good? • How and when? • Future!

3. Current research: potential leads, but sparse evidence • Methodological problems! • Few high-quality RCTs Life-course perspective Multi-factorial approach Mangialasche, Kivipelto et al., Alzheimer’s Research & therapy 2012

4. Dementia and AD: importance of life-long exposure to multiple factors ? Birth Childhood- Adult life- Old 2nd decade Middle age Transition age 0 20 60 75 Alzheimer brain Healthy brain Genetic Environment Mangialasche, Kivipelto et al., 2012

5. Protective factors Risk factors Shared factors in dementia and cardio/ cerebrovascular disease? • High education • Physical activity • Active lifestyle • Moderate alcohol intake • Antioxidants • Fish oils • Coffee • Antihypertensives • Statins • NSAIDs? • Estrogen? • ……. • Cerebrovascular disorders • Hypertension • Hypercholesterolemia • Obesity • Diabetes mellitus • Homocysteine • Smoking • Depression/stress • Head trauma • …….

6. Dementia in advanced age AD VaD Alzheimer’s disease Vascular dementia Both vascular and degenerative mechanisms often contribute to dementia development in older adults Viswanathan, et al., Neurology 2009

7. ApoE4 Magnifies Lifestyle Risk for Dementia APOE ε4 non-carriers Gene-environmental interactions APOE ε4 carriers Active Sedentary Physical activity Active Sedentary 5.5 ** IV III II I PUFA intake-quartiles IV III II I 4 * 5 * I II III IV SFA intake - quartiles I II III IV 7.1 ** 7.1 * Non-drinkers Infrequent Frequent Alcohol drinking Non-drinkers Infrequent Frequent 3.8 * Non-smokers Smokers ORs for dementia Smoking Non-smokers Smokers 3.2 * Kivipelto et al., JCMM 2008

8. Social and psychological factors Psychological factors Social+psychological Social factors Odds ratios Håkansson, Kivipelto et al., BMJ 2009Håkansson et al., manuscript

9. Risk factors: New findings Rheumatoid arthritis and other joint disorders and risk for cognitive impairment later in life Adjusted for age, sex, follow-up time, education, ApoEɛ4, medicaltreatment (NSAIDs and glucocorticoids), BMI, smoking Wallin K, Kivipelto M et al., manuscript

10. Prevention of cognitive impairment and Alzheimer’s disease • So far so good? • How and when? • Future!

11. Midlife risk profile, 20 years prediction 16 % SCORE Kivipelto et al., Lancet Neurology 2006

12. Midlife risk profile, 20 years prediction 7 % SCORE Kivipelto et al., Lancet Neurology 2006

13. Midlife risk profile, 20 years prediction 2 % SCORE Kivipelto et al., Lancet Neurology 2006

14. Randomized controlled trials

15. Dementia prevention:pharmacological and non-pharmacological RCT’s • Antihypertensive drugs • Statins • Hormone replacement therapy • NSAIDs • Nutraceuticals (folate, vitamin B12, vitamin E, vitamin C, ginkgo biloba) • Physical activity • Cognitive training Mangialasche, Kivipelto et al., 2012

16. Brain metabolism • ↑ Blood flow & glucose use • Antioxidant • ↓ Mithochondrial damage • Brain function • ↑ Synapse & synthesis Ach • ↓ β-amyloid deposition - Pro-thrombotic - Pro-inflammatory Importance of critical time window Prevention of cognitive impairment: Hormonal therapy (HT) Estrogen & Brain Negative effects Positive effects Life time Natural Menopause Early (50-60 y) Postmenopause Late (> 65 y) Postmenopause Mangialasche, Kivipelto et al., 2012

17. Alzheimer prevention Walk the talk • So far so good? • How and when? • Future!

18. Timing; starting earlier may lead to better effects • Target group;a healthy, ’too young’ population requires long follow-up and large sample sizes • Outcome measures;cognitive impairment more sensitive than conversion to dementia • Ethical issues;placebo-controlled trials for vascular factors no longer possible LESSONS LEARNED

19. Importance of multidomain approach AD is a multi-factorial disease RISK FACTORS Alcohol misuse Hypertension Dyslipidemia Obesity Vascularinsults Unhealthy diet Diabetes Smoking Neuronal damage APOE, Other genes Late-life Mid-life Adult life DEMENTIA Transition 0 20 60 75 Brain reserve Physical activity Cognitive and social activity ? Education PROTECTIVE FACTORS Mangialasche, Kivipelto et al., 2012 ICAD 2009 19

20. Objective: To reduce cognitive impairment in an at risk population through a 2-year multi-domain life-style intervention • Target population: 60-77 year old persons (n= 1200) from previous population-based non-intervention studies (FINRISK, D2D) • Inclusion criteria: Dementia Risk Score and cognitive performance

21. INTERVENTION SCHEDULE INTENSIVE INTERVENTION NUTRITION: 7 group sessions, 3 individual sessions EXERCISE: 1-2x/wk muscle 2-4x/wk aerobic EXERCISE: 2x/wk muscle 4-5x/vk aerobic EXERCISE: 2x/wk muscle strength training 5x/wk aerobic training COGNITIVE TRAINING: 9 group sessions Independent training INTERVENTION KICK-OFF RANDOMIZATION 2nd Baseline visit 1st Baseline visít MONITORING AND MANAGEMENT OF METABOLIC AND VASCULAR RISK FACTORS Nurse: Visit every 3 months, Physician: 3 additional visits Screening months 3 6 9 12 15 18 21 24 MINI- INTERVENTION REGULAR HEALTH ADVICE

22. FINGER intervention

23. 1st year preliminary results

24. 1st year preliminary results

25. OUTCOMES • Primary: • Cognitive impairment (Neuropsychological Test Battery, Trail Making & Stroop tests)and dementia • Secondary: • Depressive symptoms (Zung scale) • Vascular risk factors, morbidity and mortality • Disability (questionnaire, ADL + IADL) • Quality of life (RAND-36, 15D) • Utilization of health resources • Blood markers (i.e. inflammation, redox status, lipid and glucose metabolism, NMR metabonomics) • Brain MRI measures (n=100) and PET (n=90)

26. European Dementia Prevention Initiative EDPI http://www.edpi.org/ European Dementia Prevention Initiative • FINGER Finnish Geriatric Intervention Study to Prevent • Cognitive Impairment and Disability • preDIVA Prevention of Dementia by Intensive Vascular Care • MAPTMultidomain Alzheimer Preventive Trial

27. European Dementia Prevention Initiative www.edpi.org www.pad2020.org ADI Prevention Initiative Others? Towards worldwide action in dementia prevention!

28. 0 A 10–25% reduction in all seven risk factors could potentially prevent 1.1–3.0 million AD cases worldwide. July 2011

29. Take home points • What? • 2. When? • 3. Who? Multifactorial interventions Vascular risk factors Active lifestyle At middle age Critical time window Life-course perspective Identifying risk groups Multimorbidity Mixed neuropathology

30. Life matters! Miia Kivipelto ICAD 2010

31. ACKNOWLEDGEMENTS Grant support: Academy of Finland, Novo Nordisk Foundation, FAS, Alzheimer Association, La Carita säätiö Hilkka Soininen Alina SolomonRainer Rauramaa Tuomo Hänninen Teemu PaajanenMinna RusanenMarjo Eskelinen Miika Vuorinen Bengt WinbladLaura Fratiglioni Lars Bäckman Anders Wimo Ingemar Kåreholt Francesca MangialascheBabak Hooshmand Krister HåkanssonKarin WallinGunilla Johansson Tiina LaatikainenJaakko Tuomilehto Markku Peltonen Antti Jula Jaana LindströmTiia Ngandu Satu Ahtiluoto Timo Strandberg Riitta Antikainen