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

So far so good?

How and when?

Future!

Prevention of cognitive impairment and Alzheimer’s disease

Current research: potential leads, but sparse evidenceMethodological problems!Few high-quality RCTs

Life-course perspectiveMulti-factorial approach

Mangialasche, Kivipelto et al., Alzheimer’s Research & therapy 2012

Healthy brain Alzheimer brain?Genetic Environment

Dementia and AD: importance oflife-long exposure to multiple factors

Birth Childhood- Adult life- Old2nd decade Middle age Transition age

0 20 60 75

Mangialasche, Kivipelto et al., 2012

Shared factors in dementia and cardio/ cerebrovascular disease?

•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?•…….

Risk factors Protective factors

Alzheimer’s disease

Vascular dementiaAD VaD

Dementia in advanced age

Both vascular and degenerative mechanisms often contribute to dementia development in older adults

Viswanathan, et al., Neurology 2009

0 1 2 3 4 5 6 7 8

IVIIIIIIIVIIIIIIIIIIIIIVIIIIIIIV

ActiveSedentary

ActiveSedentary

Non-drinkersInfrequentFrequent

Non-drinkersInfrequentFrequent

Non-smokersSmokers

Non-smokersSmokers

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-carriersAPOE ε4 carriers

Kivipelto et al., JCMM 2008

ApoE4 Magnifies Lifestyle Risk for Dementia

Gene-environmental interactions

Social and psychological factors

Social factors Psychological factors Social+psychological

Odd

s ra

tios

Håkansson, Kivipelto et al., BMJ 2009Håkansson et al., manuscript

Rheumatoid arthritis and other joint disorders and risk for cognitive impairment later in life

Risk factors: New findings

Adjusted for age, sex, follow-up time, education, ApoEɛ4, medical treatment (NSAIDs and glucocorticoids), BMI, smoking

Wallin K, Kivipelto M et al., manuscript

So far so good?

How and when?

Future!

Prevention of cognitive impairment and Alzheimer’s disease

Kivipelto et al., Lancet Neurology 2006

Midlife risk profile, 20 years prediction

02468

1012141618

0-5 6-7 8-9 10-11 12-15SCORE

CAIDE Dementia Risk ScoreAge, years < 47

47-53>53

034

Education, years

≥107-90-6

023

Sex WomenMen

01

Systolic BP, mmHg

£140> 140

02

BMI, kg/m2 £30> 30

02

Cholesterol, mmol/l

£ 6.5> 6.5

02

Physical activity

ActiveInactive

01

16 %

Kivipelto et al., Lancet Neurology 2006

02468

1012141618

0-5 6-7 8-9 10-11 12-15SCORE

7 %

CAIDE Dementia Risk ScoreAge, years < 47

47-53>53

034

Education, years

≥107-90-6

023

Sex WomenMen

01

Systolic BP, mmHg

£140> 140

02

BMI, kg/m2 £30> 30

02

Cholesterol, mmol/l

£ 6.5> 6.5

02

Physical activity

ActiveInactive

01

Midlife risk profile, 20 years prediction

Kivipelto et al., Lancet Neurology 2006

02468

1012141618

0-5 6-7 8-9 10-11 12-15SCORE

2 %

CAIDE Dementia Risk ScoreAge, years < 47

47-53>53

034

Education, years

≥107-90-6

023

Sex WomenMen

01

Systolic BP, mmHg

£140> 140

02

BMI, kg/m2 £30> 30

02

Cholesterol, mmol/l

£ 6.5> 6.5

02

Physical activity

ActiveInactive

01

Midlife risk profile, 20 years prediction

Randomized controlled trials

Dementia prevention:pharmacological and non-pharmacological RCT’s

Antihypertensive drugsStatinsHormone replacement therapyNSAIDsNutraceuticals (folate, vitamin B12,

vitamin E, vitamin C, ginkgo biloba)

Physical activityCognitive training

Mangialasche, Kivipelto et al., 2012

Prevention of cognitive impairment:Hormonal therapy (HT)

Negative effects

Positive effects

Estrogen & Brain

- Pro-thrombotic- Pro-inflammatory

Brain metabolism- ↑ Blood flow & glucose use- Antioxidant- ↓ Mithochondrial damage

Brain function- ↑ Synapse & synthesis Ach- ↓ β-amyloid deposition

Natural Menopause

Early (50-60 y) Postmenopause

Late (> 65 y) Postmenopause

Life time

Importance of critical time window

Mangialasche, Kivipelto et al., 2012

So far so good?

How and when?

Future!

Alzheimer preventionWalk the talk

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

ICAD 2009 19

Alcoholmisuse

AD is a multi-factorial disease

Neuronal damage

Brain reserve

APOE,Other genes

DEMENTIA

Physicalactivity

RISK FACTORS

?

0 20 60 75

Adult life Mid-life Late-life

Unhealthydiet

Transition

Cognitive andsocial activity

EducationPROTECTIVE FACTORS

Smoking

Hypertension Dyslipidemi

aObesity Vascular insultsDiabete

s

Importance of multidomain approach

Mangialasche, Kivipelto et al., 2012

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

Scre

enin

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sít

2nd

Bas

elin

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sit

RA

ND

OM

IZAT

ION

INTENSIVE INTERVENTION

REGULAR HEALTH ADVICE

INTE

RVE

NTI

ON

KIC

K-O

FF

MINI-INTERVENTION

3 6 9 12 15 18 21 24

NUTRITION: 7 group sessions,

3 individual sessions

COGNITIVE TRAINING:9 group sessions

Independent training

EXERCISE:1-2x/wk muscle2-4x/wk aerobic

EXERCISE:2x/wk muscle

4-5x/vk aerobic

EXERCISE:2x/wk muscle strength training

5x/wk aerobic training

MONITORING AND MANAGEMENT OF METABOLIC AND VASCULAR RISK FACTORS

Nurse: Visit every 3 months, Physician: 3 additional visits

months

INTERVENTION SCHEDULE

FINGER intervention

1st year preliminary results

Group N Baseline 12 month p-value

Weight, kg Intervention 213 81.8 80.6 0.04Control 216 81.9 81.6

BMI, kg/m2 Intervention 213 28.9 28.5 0.04Control 216 28.9 28.7

SBP, mmHg Intervention 212 142.1 138.0 0.81Control 215 142.4 138.2

DBP, mmHg Intervention 212 81.9 80.6 0.33Control 215 81.6 80.9

1st year preliminary results

Group N Baseline 12 month p-valueFasting glucose Intervention 209 6.13 6.14 0.32

mmol/L Control 216 6.10 6.24OGTT 120min Intervention 179 7.03 6.97 0.09mmol/L Control 181 6.99 7.23Total cholesterol Intervention 209 5.13 5.05 0.04mmol/L Control 216 5.12 5.19HDL Intervention 209 1.42 1.42 0.61

mmol/L Control 216 1.43 1.42LDL Intervention 209 3.07 3.04 0.03mmol/L Control 216 3.06 3.15Triglycerides Intervention 209 1.40 1.32 0.44

mmol/L Control 216 1.38 1.37

Primary:Cognitive impairment (Neuropsychological Test

Battery, Trail Making & Stroop tests) and dementia

Secondary:Depressive symptoms (Zung scale)Vascular risk factors, morbidity and mortalityDisability (questionnaire, ADL + IADL) Quality of life (RAND-36, 15D)Utilization of health resourcesBlood markers (i.e. inflammation, redox status, lipid and

glucose metabolism, NMR metabonomics) Brain MRI measures (n=100) and PET (n=90)

OUTCOMES

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

EDPIhttp://www.edpi.org/

European Dementia Prevention Initiative

www.edpi.org

www.pad2020.org

Towards worldwide action in dementia prevention!

ADI Prevention InitiativeOthers?

0

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

July 2011

1. What?

2. When?

3. Who?

Multifactorial interventionsVascular risk factorsActive lifestyle

Take home points

At middle age Critical time windowLife-course perspective

Identifying risk groups MultimorbidityMixed neuropathology

Life matters!

Miia Kivipelto ICAD 2010

Tiina LaatikainenJaakko TuomilehtoMarkku PeltonenAntti JulaJaana LindströmTiia NganduSatu Ahtiluoto

Hilkka SoininenAlina SolomonRainer RauramaaTuomo HänninenTeemu PaajanenMinna RusanenMarjo EskelinenMiika Vuorinen

Timo StrandbergRiitta Antikainen

Bengt WinbladLaura FratiglioniLars BäckmanAnders WimoIngemar KåreholtFrancesca MangialascheBabak HooshmandKrister HåkanssonKarin WallinGunilla Johansson

ACKNOWLEDGEMENTSGrant support: Academy of Finland, Novo Nordisk Foundation, FAS, Alzheimer Association, La Carita säätiö