1. 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.

2. 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.

3. 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

4. ? 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

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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?

11. Midlife risk profile, 20 years prediction
CAIDE Dementia Risk Score
Age, years
< 47
47-53
>53 3 4
Education, years ≥
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

12. Midlife risk profile, 20 years prediction
CAIDE Dementia Risk Score
Age, years
< 47
47-53
>53 3 4
Education, years ≥
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

13. Midlife risk profile, 20 years prediction
CAIDE Dementia Risk Score
Age, years
< 47
47-53
>53 3 4
Education, years ≥
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

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

15. 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

16. 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

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

18. 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….

19. 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

20. 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: 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 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.

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
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

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

23. 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)

24. 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

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)
Several outcomes; total benefit, mechanisms etc

26. European Dementia Prevention Initiative
EDPI
European Dementia Prevention Initiative
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. > Target group, interventions, droup outs, differences in different countires. Used to initiate larger multinational RCTs. To what extent multidomain intervention may delay cog impairment.

27. Towards worldwide action in dementia prevention!
European Dementia Prevention Initiative
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!

28. 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

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
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 with other diseases may affect cognition. mixed neuropatology.
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 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