Can we prevent Alzheimer s disease and other memory disorders? Tiia Ngandu, MD, PhD Diabetes Prevention Unit, National Institute for Health and Welfare and Alzheimer s Disease Research Center,Karolinska Institutet, Sweden
Prevention of cognitive impairment and Alzheimer s disease Memory disorders Risk Factors Interventions
Dementia / Memory disorders Dementia: impaired memory and other cognitive functions, disability Causes: Alzheimer s disease 6-7 % Vascular cognitive impairment 15 % Lewy Body Disease 15 % Others 5 % Memory disorders
Occurrence of dementia Prevalence increases with age 65-69 years 1.5% >85 years 35% >95 years up to 6% 35.6 million people with dementia in 21 115.4 million in 25 2/3 in low and middle income countries (World Alzheimer Report 29)
Burden of dementia Patient Informal care (family) Medical care Social care (residential or nursing homes) Estimated total costs of 64 billion USD in 21 (1% of world s gross domestic product) (World Alzheimer Report 21)
Prevention of AD: postponing the onset of the disease Delay (years) 8.5 1 2 5 6 4 2 US prevalence of AD (millions) 1997 27 217 227 Year 237 247 Brookmeyer et al., 1998, Jorm 25
Managing Alzheimer s Disease A Lifelong Commitment Onset of MCI* Clinical diagnosis of AD 75 5 25 % of end-stage AD1 Asymptomatic Preclinical Clinical phase phase phase 4 5 6 7 8 Age (years) Estimated start of neuropathological changes *MCI - mild cognitive impairment Modified from PJ Visser, 2
FINRISK The FINRISK Study, North Karelia Project Aim: Integrate memory disorders into the existing framework
Risk and protective factors for dementia/ad Risk factors Cerebrovascular disorders Hypertension Hypercholesterolemia Obesity Diabetes mellitus Homocysteine Smoking Depression Head trauma Protective factors High education Physical activity Active lifestyle Moderate alcohol intake Antioxidants Fish oils Coffee Antihypertensives Statins NSAIDs? Estrogen?
What goes around comes around Risk relationship FACTOR Reverse causality DISEASE i.e. Cholesterol, Blood pressure, BMI CAIDE, Solomon A et al. Neurology 27, Neurobiol Aging 29 Honolulu Asia Aging Study, Stewart R et al. Arch Neurol 27 Kungsholmen Project, Qiu C et al. Stroke 24 Gothenburg Study, Skoog I et al. Lancet 1996, Gustafson D et al. Neurology 29 Life-course perspective is needed when assessing the risk factors for AD
ApoE4 Magnifies Lifestyle Risk for Dementia Physical activity PUFA intakequartiles SFA intake - quartiles Alcohol drinking Active Sedentary Active Sedentary IV III II I IV III II I I II III IV I II III IV Non-drinkers Infrequent Frequent Non-drinkers Infrequent Frequent 4 * 3.8 * APOE ε4 non-carriers APOE ε4 carriers 5.5 ** 5 * 7.1 ** 7.1 * Non-smokers Smokers Smoking Non-smokers Smokers 3.2 * ORs for dementia Kivipelto et al., JCMM 28 1 2 3 4 5 6 7 8
Midlife leisure time physical activity and dementia/ad Dementia AD OR.47.35 (95% CI) (.25-.9) (.16-.8) Rovio, et al., Lancet Neurology 25 β- coefficient Total brain volume.21 (p<.1) Grey matter volume White matter volume β.15 (p<.1) Brain derived neurotrophic factor (BDNF): β.29 a marker of cognitive (p<.1) functioning? Rovio, et al. Neurobiol Aging 29 Komulainen,et al., 28
Leisure activities RR (95%CI) for dementia High mental score.71 (.49-1.3) High physical score.61 (.42-.87) High social score.68 (.47-.99) Karp et al, 25
6 The risks of unmarried life OR (95% CI) for MCI, AD and dementia in persons without partner at midlife 5 4 3 2 1 Håkanson K et al., BMJ 29 Ref MCI AD Dementia Controlled for age, sex, education, APOE ε4, BP, cholesterol, BMI, occupation, occupational physical activity
Age Formal education Sex Systolic BP BMI Cardiovascular Risk Factors, Aging and Incidence of Dementia Total cholesterol Physical activity Dementia Risk Score < 47 years 47-53 years > 53 years 1 years 7-9 years -6 years Women Men < 14 mm Hg > 14 mm Hg < 3 kg/m2 > 3 kg/m2 6.5 mmol/l > 6.5 mmol/l Active Inactive 3 4 2 3 1 2 2 2 1 Kivipelto, Ngandu et al., Lancet Neurol 26
Probability of dementia according to the risk score category SCORE Risk -5 1. % 6-7 1.9 % 8-9 4.2 % 1-11 7.4 % 12-15 16.4 % Kivipelto, Ngandu et al. Lancet Neurology 26
Midlife risk profile, 2 years prediction CAIDE Dementia Risk Score Age, years < 47 47-53 >53 3 4 Education, years Sex 1 7-9 -6 Women Men <14 > 14 Systolic BP, mmhg BMI, kg/m 2 < 3 > 3 Cholesterol, 6.5 mmol/l > 6.5 Physical activity Active Inactive 2 3 1 2 2 2 1 18 16 14 12 1 8 6 4 2 16 % -5 6-7 8-9 1-11 12-15 SCORE Kivipelto, Ngandu et al., Lancet Neurology 26
Randomized controlled trials
SUMMARY OF EARLIER RCT S INTERVENTION STUDIES FINDINGS Antihypertensives Statins Cholinesterase inhibitors Memantine Estrogen, Estrogen+Progestin Raloxifene DHEA SCOPE, SHEP, Syst- Eur, PROGRESS Heart Protection Study, PROSPER Cochrane review 28 Schumaker JAMA 23, 24 Cohcrane review 22 Ns, except protective in 1 follow-up study, and 1 study with history of vascular disease Ns Ns Increased risk/ Ns Ns Ns
SUMMARY OF EARLIER RCT S INTERVENTION STUDY FINDINGS NSAID s ADAPT 29 Increased risk Aspirin Price 28 Ns Ginkgo biloba DeKosky JAMA 28 Ns Multivitamins MAVIS 27 Ns Vitamin E Petersen NEJM 25 Ns Vitamin B and folate Kang 28 Ns McMahon 26 Vitamin C Ns Beta carotene Omega-3 fatty acids Ns Ns Cognitive training ACTIVE Positive effect on targeted function Physical activity Lautenschlager 28 Small positive Dr s Extra effect Social engagement Diet
Recipe for prevention trials? Timing; starting earlier may lead to better effects Target group; a healthy, too young population will require very long follow-up times and large sample sizes Outcome measures; cognitive impairment may be a better measure than conversion to dementia Ethical issues; placebo-controlled trials regarding pharmacological treatment of cardiovascular disease risk factors are not possible
AD is a multi-factorial disease: target several risk factors simultaneously for an optimal preventive effect RISK FACTORS APOE, Other genes Alcohol misuse Unhealthy diet Physical activity Adult life Mid-life Late-life 2 6 75 Education Hypertension Dyslipidemia Obesity Vascular insults Diabetes Smoking Neuronal damage Transition Cognitive and social activity PROTECTIVE FACTORS Brain reserve? DEMENTIA 22
Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability Objective: To reduce cognitive impairment in an at risk population through a 2-year multi-domain life-style intervention Target population: 6-77 year old persons (n= 12) from previous population-based nonintervention studies (FINRISK, D2D) Time schedule: Screening began in September 29 and was completed in 211. The intervention will be completed in the beginning of 214
Study design: A multi-center (6 sites) single-blind RCT enrolling 12 persons randomized into 2 groups (multidomain intervention or regular health advice) for a 2-year period. Extended follow-up to 7 years. Multidomain intervention: i) nutritional guidance ii) increased physical activity iii) cognitive training and iv) intensive monitoring and management of vascular risk factors Primary outcome: Cognitive impairment 24
INCLUSION CRITERIA: persons at risk of dementia/ cognitive decline AND Dementia Risk score > 6 Based on risk factors assessed in earlier population surveys: Age, Education, Sex, SBP, Cholesterol, BMI, Physical Activity (Kivipelto et al., Lancet Neurology 26) Cognitive performance at the mean level or slightly lower than expected for age CERAD: 1) Word List Immediate Memory task (1 words x3) < 19 words AND/OR 2) Word List Delayed Recall < 75% AND/OR 3) MMSE < 26
INTERVENTION SCHEDULE INTENSIVE INTERVENTION Recruitment (Dementia risk score) Screening (Nurse: CERAD; Physician) Baseline visit (NTB) RANDOMIZATION INTERVENTION KICK-OFF NUTRITIONAL COUNCELING: 7 group & 3 individual sessions PHYSICAL ACTIVITY: 1-2x/wk muscle strength & 1-4x/wk aerobic training COGNITIVE TRAINING: 9 group sessions, Independent training 3x/wk 6mo PHYSICAL ACTIVITY: 2-3x/wk muscle strength & 5-6x/wk aerobic training COGNITIVE TRAINING: 2 group sessions, Independent training 3x/wk 6mo MANAGEMENT OF METABOLIC AND VASCULAR RISK FACTORS 6 nurse visits, 4 physician visits Follow-up visit Follow-up visit Follow-up visit Month 3 6 9 12 15 18 21 24 MINI- INTERVENTION Follow-up visit Follow-up visit REGULAR HEALTH ADVICE Follow-up visit
OUTCOMES Primary: Cognitive impairment (Neuropsychological Test Battery, Trail Making & Stroop tests) Secondary: Dementia (after 7 years) 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=1) and PET (n=9)
RELEVANCE OF A MULTI-DOMAIN INTERVENTION Will test to what extent a multi-domain intervention may delay cognitive impairment and dementia onset in people at an increased risk Is an innovative approach to delay cognitive impairment while simultaneously intervening upon several risk factors of other major diseases Will provide data urgently needed for health education and community planning
EDPI European Dementia Prevention Initiative FINGER prediva MAPT Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability Prevention of Dementia by Intensive Vascular Care Multidomain Alzheimer Preventive Trial
A 1 25% reduction in all seven risk factors could potentially prevent 1.1 3. million AD cases worldwide. July 211
CONCLUSIONS Can we prevent/delay memory disorders? Vascular factors: Hypertension Diabetes Obesity Starting from middle age Special focus on ApoE e4 carriers Be active and maintain an active life Social integration Physical activities Mental activities
Acknowledgements Grant support: Academy of Finland, La Carita Foundation, American Alzheimer Association, Novo Nordisk Fonden, Alzheimer s Research and Prevention Foundation, The Social Insurance Institution of Finland, Juho Vainio Foundation Miia Kivipelto Tiina Laatikainen Markku Peltonen Antti Jula Jaana Lindström Satu Pajala Satu Ahtiluoto Jenni Lehtisalo Liisa Saarikoski Pirjo Saastamoinen Marko Grönholm Esko Levälahti Päivi Valve Hilkka Soininen Tuula Pirttilä Rainer Rauramaa Raimo Sulkava Alina Solomon Tuomo Hänninen Teemu Paajanen Jaakko Tuomilehto Timo Strandberg Riitta Antikainen Lars Bäckman Turku PET Centre Juha Rinne Anna Stigsdotter Neely 32