Prevention of Alzheimer’s disease – is it possible? Miia Kivipelto, MD, PhD Professor Karolinska Institutet Alzheimer Disease Research Center (KI-ADRC) and Karolinska University Hospital, Sweden Thank you for the organizers for the inivitation. I am very happy to be here today and talk about Alzheimer prevention.

Prevention of cognitive impairment and Alzheimer’s disease So far so good? How and when? Future! What is the current status of evidence and some new findings especially from our Scandinavian studies concerning modifiable risk factors. More practical issues in prevention, what we should do, and when? Introduce multidomain interventions and future directions in the field.

Life-course perspective Multi-factorial approach Current research: potential leads, but sparse evidence Methodological problems! Few high-quality RCTs 1. We how have been working with Alzheimer prevention surely think that we have already come a quite long way in the fight against Alzheimer. There are many positive findings, more optimistic picture….. 2. In this sense the NIH state of the science report presented by an independent panel of experts not working in AD field was quite disappointing. We still have a long way to go. Not enough evidence to give specific recommendations to AD prevention. Can be discussed; good t have in mind that AD prevention field is still young, many studies methodological limitations; how to define AD, shot follow-up times. Gold standard in evidence-based medicine is RCT; still lacking is AD prevention field (we do not have enough). 3. Further, there are 2 important concepts that are needed for managing AD and moving the prevention field forward; life-course perpective and muti-factorial apparoach Life-course perspective Multi-factorial approach Mangialasche, Kivipelto et al., Alzheimer’s Research & therapy 2012

? Genetic Environment Dementia and AD: importance of life-long exposure to multiple factors Birth Childhood- Adult life- Old 2nd decade Middle age Transition age 20 60 75 ? Healthy brain Alzheimer brain This is because AD is a complex disporders, muti-factorial and heterogenious. Besodes genetic factors, exposure to various environmental risk and protective factors during the whole life course affects if we get and when we get the disease. That is why lifecourse perspective and multi-factorial approach are important. Positive; gives several times windows and several targets for interventions. Genetic Environment Mangialasche, Kivipelto et al., 2012

Shared factors in dementia and cardio/ cerebrovascular disease? Risk factors Protective factors Cerebrovascular disorders Hypertension Hypercholesterolemia Obesity Diabetes mellitus Homocysteine Smoking Depression/stress Head trauma ……. High education Physical activity Active lifestyle Moderate alcohol intake Antioxidants Fish oils Coffee Antihypertensives Statins NSAIDs? Estrogen? ……. And we have indeed increasing data from long-term epi studies that dementia and AD have several possible modifiable/treatable risk factors. I have listed the most important ones, highlighted with pink factors where we have strongest evidence. List is more positive compared to NIH list. Especially vascular risk factors. List of protective factors is getting longer. Nice activities; active lifestyle, good food, some coffee….. It is also interesting that many of these factors are shared with cardio and cerebrovascular diseases.

Dementia in advanced age VaD Alzheimer’s disease Vascular dementia Targeting these factors, we may prevent or postpone several aging related disorders. Both AD and VaD. This is important because especially among elderly persons, destingtion between AD and VaD is not so clear. Most persons have mixed brain lesions. Given this, and how common the risk factors are, many still untreated, prevention or postponing dementia onset should be realistic goal. Main subtype dementia: Clinically, Alzheimer’s disease (AD) and vascular dementia (VaD); Pathologically, mixed dementia may be the most common type of dementia, especially among very old people. AD and VaD often cohexist in subejcts with dementia, and they share several risk and protective factors. Both vascular and degenerative mechanisms often contribute to dementia development in older adults Viswanathan, et al., Neurology 2009

Gene-environmental interactions ApoE4 Magnifies Lifestyle Risk for Dementia IV III II I Active Sedentary Non-drinkers Infrequent Frequent Non-smokers Smokers ORs for dementia Physical activity PUFA intake-quartiles SFA intake - quartiles Alcohol drinking Smoking 5.5 ** 4 * 5 * 7.1 ** 7.1 * 3.8 * 3.2 * APOE ε4 non-carriers APOE ε4 carriers Now, what we are working with is try to refine the evidnece concerning risk factors. One important aspect; not only genes or environment but there are several intercations..... ApoE4, the most important genetic risk factor for AD and lifetsyle factors. The effect of unhelathy lifestyle factors more pronounced among the ApoE4 carriers. Blue bars. Healhty lifetsyle can be recommended for all, especially for those with genetic suspcetability. Kivipelto et al., JCMM 2008

Social and psychological factors Social factors Psychological factors Social+psychological Odds ratios Besides biological factors, we have studies recently also more social and psychological factors in relation to AD. Social factors: living alone, especailly beining widowed significant risk factors Psychoilogical: Depressive signs: Additive effect: combination strong risk. Psychosocial interventions, see these risk groups, people living alone, widowed. Activate/stimulate – may have great impcat for well beining but also in sence decreasing risk Håkansson, Kivipelto et al., BMJ 2009 Håkansson et al., manuscript

Risk factors: New findings Rheumatoid arthritis and other joint disorders and risk for cognitive impairment later in life Finally, there maybe also novel risk factors. Our new study highlights the role of chronic inflmaatarory diseases as risk factor for AD. Interesting given that inflammation has been suggested to be an early pathopyciological mechanim in AD and again, this opens new targets and possibilities for interventions. Adjusted for age, sex, follow-up time, education, ApoEɛ4, medical treatment (NSAIDs and glucocorticoids), BMI, smoking Wallin K, Kivipelto M et al., manuscript

Prevention of cognitive impairment and Alzheimer’s disease So far so good? How and when? Future! Parcatical issues in prevention: what should be do and when?

Midlife risk profile, 20 years prediction CAIDE Dementia Risk Score Age, years < 47 47-53 >53 3 4 Education, years ≥10 7-9 0-6 0 2 3 Sex Women Men 0 1 Systolic BP, mmHg 140 > 140 0 2 BMI, kg/m2 30 > 30 Cholesterol, mmol/l  6.5 > 6.5 Physical activity Active Inactive 1 16 % Start as early as possible, already at midlife. Risk scores could be used to identify high risk individuals and target interventions for those most at risk. Can also be used as educational and motivational tools. Here is an example of Caide dementia risk score based on risk factors at midlife , around 50 years. For example, here is a risk profile for a 50-years old male who have 8 years of education, high BP, chol and BMi and is also physically inactive. SCORE Kivipelto et al., Lancet Neurology 2006

Midlife risk profile, 20 years prediction CAIDE Dementia Risk Score Age, years < 47 47-53 >53 3 4 Education, years ≥10 7-9 0-6 0 2 3 Sex Women Men 0 1 Systolic BP, mmHg 140 > 140 0 2 BMI, kg/m2 30 > 30 Cholesterol, mmol/l  6.5 > 6.5 Physical activity Active Inactive 1 7 % What happens ig he can reduce BP and increase physical activity SCORE Kivipelto et al., Lancet Neurology 2006

Midlife risk profile, 20 years prediction CAIDE Dementia Risk Score Age, years < 47 47-53 >53 3 4 Education, years ≥10 7-9 0-6 0 2 3 Sex Women Men 0 1 Systolic BP, mmHg 140 > 140 0 2 BMI, kg/m2 30 > 30 Cholesterol, mmol/l  6.5 > 6.5 Physical activity Active Inactive 1 2 % Further….. Educational/motivational tool We are talking only about risks. At individual level it is never possible to say if someone will get AD. Only exetion are causative genetc mutations but they are very rare. There are always persons how will get AD even if they do not have any of these factors. Genes, other factors. Risk score is important because it can estimate the probability and presents the main modifiable risk factors common in the population. SCORE Kivipelto et al., Lancet Neurology 2006

Randomized controlled trials Gold standard to show the effect of an intervention. In dementia prevention field, very few positive studies.

Antihypertensive drugs Statins Hormone replacement therapy NSAIDs 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 Strongest evidence for antihypertensive medications. For other agents like statins, estrogen and gingo there is no clear evidence for protective effect. For HRT, the results were actually the opposite indicating increased risk for cog impairment. For physical activity and cog training there is some evidence about positive effects on cognition but the impact seems to be modest at best and we do not no yet what are the implications in everyday living and if these interventions really can prevent or postpone dementia onset. Mangialasche, Kivipelto et al., 2012

Importance of critical time window Prevention of cognitive impairment: Hormonal therapy (HT) Estrogen & Brain Brain metabolism ↑ Blood flow & glucose use Antioxidant ↓ Mithochondrial damage Brain function ↑ Synapse & synthesis Ach ↓ β-amyloid deposition - Pro-thrombotic - Pro-inflammatory Positive effects Negative effects Life time One important aspect in interventions is timing. As an example estrogen; we have experimental evidence that estrogen may improve brain metabolism and function in several ways. On the other hand it may also have negative effects. The balance may depend on timing of the intervention. If staterd eraly, around menipause, protective effects. Later most harmful effects. Critical time window. Need to be studies further for HRT and other interventions. Natural Menopause Early (50-60 y) Postmenopause Late (> 65 y) Postmenopause Mangialasche, Kivipelto et al., 2012

Alzheimer prevention Walk the talk So far so good? How and when? Future! Where to go from here?

LESSONS LEARNED 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 We have learned several lessions….

Importance of multidomain approach AD is a multi-factorial disease RISK FACTORS Alcohol misuse Hypertension Dyslipidemia Obesity Unhealthy diet Vascular insults Diabetes Smoking Neuronal damage APOE, Other genes Adult life Mid-life Late-life DEMENTIA Transition 20 60 75 Physical activity Cognitive and social activity Brain reserve Multifactorial condition; target several risk factors simultanneously for an optimal preventive effect. ? Education PROTECTIVE FACTORS Mangialasche, Kivipelto et al., 2012 ICAD 2009 19

Inclusion criteria: Dementia Risk Score and cognitive performance 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 an ongoing multi-domain, multi-center RCT enrolling 1200 independently living 60-77 years old persons from 6 cities in Finland. Inclusion is done according to CAIDE Dementia Risk Score and CERAD cognitive test battery. Criteria select elderly at risk for cognitive impairment and disability, who are most likely to benefit from the intervention. Persons with dementia/substantial cognitive decline are excluded FINGER. Generalize to results for the population.

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 1st Baseline visít 2nd Baseline visit MONITORING AND MANAGEMENT OF METABOLIC AND VASCULAR RISK FACTORS Nurse: Visit every 3 months, Physician: 3 additional visits Screening The 2-year multi-domain intervention has 4 components: nutrition; physical activity; cognitive and social activity; monitoring of metabolic/vascular risk factors (interventions group receiving all components). The intervention is based on the best available knowledge; focus is on simultaneously addressing several common modifiable risk factors to obtain an optimal prevention effect. Group and individual sessions. Aerobic and muscle experice, balance training. Increasing intensitity. The use of computer-based exercises enables individually adjusted and progressive difficulty levels to enable maximal effect of training. Programs are tailored according to participants’ needs and health status, but are given within a carefully planned framework months 3 6 9 12 15 18 21 24 MINI- INTERVENTION REGULAR HEALTH ADVICE

FINGER intervention Motivated. Working in groups give some social stimulation and extra motivation. Randomized all 1200 persons. Drop out rate low, only xx.

1st year preliminary results Group N Baseline 12 month p-value Weight, kg Intervention 213 81.8 80.6 0.04 Control 216 81.9 81.6 BMI, kg/m2 28.9 28.5 28.7 SBP, mmHg 212 142.1 138.0 0.81 215 142.4 138.2 DBP, mmHg 0.33 80.9 Baseline data: elevated risk factors and unhealthy lifestyle factors: window of opportunity for the intervention. Preliminary data analysis support the beneficial effects of the multidomain intervention: compared to the control group, subjects in the intervention arm have had a significant weight loss and BMI reduction and reduced plasma levels of total cholesterol. Trend for imrovment in glucose metabolism (detected by OGTT)

1st year preliminary results Group N Baseline 12 month p-value Fasting glucose Intervention 209 6.13 6.14 0.32 mmol/L Control 216 6.10 6.24 OGTT 120min 179 7.03 6.97 0.09 181 6.99 7.23 Total cholesterol 5.13 5.05 0.04 5.12 5.19 HDL 1.42 0.61 1.43 LDL 3.07 3.04 0.03 3.06 3.15 Triglycerides 1.40 1.32 0.44 1.38 1.37

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) Several outcomes; total benefit, mechanisms etc

European Dementia Prevention Initiative EDPI European Dementia Prevention Initiative http://www.edpi.org/ FINGER Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability preDIVA Prevention of Dementia by Intensive Vascular Care MAPT Multidomain Alzheimer Preventive Trial Need for international collaboration to move the dementia prevention field forwrad! In Europe, 2 other large RCTs: similarities but also important differences. EDPI: share experiencesm and data. > 6000 . Target group, interventions, droup outs, differences in different countires. Used to initiate larger multinational RCTs. To what extent multidomain intervention may delay cog impairment.

Towards worldwide action in dementia prevention! European Dementia Prevention Initiative www.edpi.org www.pad2020.org ADI Prevention Initiative Others? It is very important that all inititives collaborate concrete and move towards worldwide action. We need to walk the talk ! Towards worldwide action in dementia prevention!

It has been recently estimated that up to 50% of AD are related to modifiable risk factors. A 10–25% reduction in such factors could potentially prevent up to 3 million AD cases worldwide, with the combined reduction having the greatest impact on dementia prevalence. The ongoing RCTs will show if this is possible and what are the best ways to modify risk factors. Crucial for helath eductaion and commuinity planning. A 10–25% reduction in all seven risk factors could potentially prevent 1.1–3.0 million AD cases worldwide. July 2011

Take home points What? 2. When? 3. Who? Multifactorial interventions Vascular risk factors Active lifestyle At middle age Critical time window Life-course perspective Is it possible to prevent AD? Well, what do you think? Optimistic. Maybe not prevent, postpone the onset. Very important. Take home points what, when and who? 1. What? To have an otimal effect, the intervention needs to be multifactorial. Main components: vascular at midlfie, maintain active lifestyle even later in life: mental, social and physical activities 2. as early as possible, chiled, education and liftle habits. Latest midilfe. Critical time windows for some interventions. Never too late. We can always do something… 3. Who should be the target? Healthy lifetyle for all, risk groups. How to identify. Risk score, can be further developed. Important to realize elederly persons, 70% over 75+. with other diseases may affect cognition. mixed neuropatology. Identifying risk groups Multimorbidity Mixed neuropathology

Life matters! Miia Kivipelto ICAD 2010

ACKNOWLEDGEMENTS Grant support: Academy of Finland, Novo Nordisk Foundation, FAS, Alzheimer Association, La Carita säätiö Hilkka Soininen Alina Solomon Rainer Rauramaa Tuomo Hänninen Teemu Paajanen Minna Rusanen Marjo Eskelinen Miika Vuorinen Bengt Winblad Laura Fratiglioni Lars Bäckman Anders Wimo Ingemar Kåreholt Francesca Mangialasche Babak Hooshmand Krister Håkansson Karin Wallin Gunilla Johansson Tiina Laatikainen Jaakko Tuomilehto Markku Peltonen Antti Jula Jaana Lindström Tiia Ngandu Satu Ahtiluoto Timo Strandberg Riitta Antikainen