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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. Prevention of cognitive impairment and Alzheimer’s disease . So far so good? How and when? - PowerPoint PPT Presentation
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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
g1s
t Bas
elin
e vi
sít
2nd
Bas
elin
e vi
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