diabetes prevention studies and implications for alzheimer research | dr. jaakko toumilehto

Dr. Jaakko TuomilehtoProfessor National Institute for Health and Welfare, Helsinki, Finland;

King Abdulaziz University, Jeddah, Saudi Arabia; Danube University Krems, Krems, Austria

Monday, September 16, 13

Diabetes prevention studies and implications for

Alzheimer research

Dr. Jaakko TuomilehtoMonday, September 16, 13

0

7.5

15

22.5

30Prevalence of D

iabetes (%)1.1 2.7

5.79

12.811.8

1.5 1.9 5.19.5

14.5

21.5

30 - 39 40 - 49 50 - 5960 - 69

70 - 7980 - 89

Dr. Jaakko Tuomilehto

Prevalence of known diabetes (%) in Europe by age-group, DECODE

Male Female



The International Diabetes Federation Diabetes Atlas 5th Edition

A summary of the figures and key

findings



Diabetes: the Top 10s (prevalence, % of the population)



Diabetes: Regional overview and projections


• 366 million people have diabetes in 2011; by 2030 this will have risen to 552 millio

• The number of people with type 2 diabetes is increasing in every country

• 80% of people with diabetes live in low-and middle-income countries

• The greatest number of people with diabetes are between 40 to 59 years of age

• 183 million people (50%) with diabetes are undiagnosed

• Diabetes caused 4.6 million deaths in 2011

• Diabetes caused at least USD 465 billion dollars in healthcare expenditures in 2011; 11% of total healthcare expenditures in adults (20-79 years)

• 78,000 children develop type 1 diabetes every year


Diabetes: the global burden



Undiagnosed diabetes



Diabetes and Alzheimer’s Disease - similarities

• Similar lifestyle risk factors• Both increase steeply with age• Diabetes is an independent risk factor for ! Alzheimer Disease and Vascular Dementia• Long asymptomatic preclinical phase• Co-morbidities common and similar• Both reduce life expectancy and quality of life



Common Modifiable Risk Factors for Type 2 Diabetes and Dementia

• Obesity / weight gain• Central obesity• Physical inactivity • Smoking• Fatty liver• Depression• Poor sleep quality• Hypertension

• Dietary Factors (risk increase/decrease) - Carbohydrate quality - Fat quality - Glycemic index - Whole grain / cereal fibers - Alcohol - Coffee - Fish



Trends in Body Mass Index and DM in Finland

BMI-Men BMI-Women

0

10

20

30

40

1969 1976 1986 1996 2000 2012

Diabetes

0

10

20

30

40

1969 1976 1986 1996 2000 2012

Diabetes

? ?



Diabetes and Alzheimer disease

Several epidemiological studies have suggested that diabetes increases the risk of Alzheimer disease

Positive association:Yoshitake et al., 1995Leibson et al., 1997Brayne et al., 1998 Ott et al., 1999 Peila et al., 2002 Yamada et al 2003 Arvanitakis et al., 2004Luchsinger et al., 2005Akomolafe et al., 2006Irie et al., 2008Xu et al. 2009Ahtiluoto et al. 2010

No association:Curb et al., 1999MacKnight et al,. 2002Hassing et al., 2002Xu et al., 2004Hayden et al., 2006



Cognitive deficits in non-demented people with Diabetes (1)

Compared to age- matched controls elderly (above 70 yrs) Patients with Diabetes show deficits in :

• global cognitive scores• perceptual speed• verbal episodic memory• semantic memory• executive functions

Duration of Diabetes is associated with these cognitive deficits

Cognitive deficits are associated with lower functional capability and higher mortality



Cognitive deficits in non-demented people with Diabetes (2)

Whitehall II study

Kumari M, Marmot M, Neurology 2005

N=5600!Follow-up 5 yrs

Diabetes associated with poorer performance on inductive cognitive reasoning:

! Risk !2.45 fold for males ! ! 1.83 fold for females



Morphologic brain changes in non-demented people with Diabetes/disturbed glucose tolerance

• den Heijer T et al , Diabetologia 2003: Hippocampal atrophy

• Hassing LB, et al, Age Ageing 2004: General cortical brain aaatrophy in conjunction with hypertension

• Convit A et al, PrclNatl Acad Sci USA 2003: Reduced glucose ttttolerance correlates with poor memory perfomance and hhhippocampal atrophy



Diabetes Mellitus increases the risk of Dementia (1)

Ott A et al. Diabetes Mellitus and the Risk of Dementia. 1999; 53:1937-1942

Rotterdam Study

Prospective population-based cohort study among 6370 elderly subjects.Non-demented participants were followed up average for 2,1 yearsEstimation of RR with proportional hazard regression adjusted for age, sex and possible confounders.

During FU 126 patients (2%) became demented of whom 89 had AD.

DM almost doubled the risk of dementia RR 1.9 (1.3 - 2.8) and AD RR 1.9 (1.2 - 3.1)




Luchsinger J A, et al. Diabetes Mellitus and Risk of Alzheimer‘s Disease and Dementia with Stroke in a Multiethnic Cohort. Am J Epidemiol 2001; 154:635-41.

1262 elderly subjects (>~ 65 yrs) without dementia at baseline (1991-1996) were followed up for an average of 4,3 years (1992-1997).Outcomes: incident Alzheimer‘ disease (AD) and dementia associated with stroke. Prevalence of diabetes was 20% at baseline.

RR of AD among subjects with DM ! ! !

RR of AD + cognitive impairment without dementia in persons with DM (without stroke)

RR of stroke-associated dementia in persons with DM

1.3 (0.8-1.9)

1.6 (1.2-2.1)

3.4 (1.7- 6.9)




Xu W.L. et al. Diabetes mellitus and the risk of dementia in the Kungsholmen project. Neurology 2004; 63: 1181-1186

Kungsholmen project, Sweden

A dementia-free cohort of 1301 community dwellers aged 75 years and older in Stockholm.Longitudinally examined twice over 6 years to detect dementia cases. At baseline 114 (8,8%) had Diab

- 350 subjects developed dementia (260 Alzheimer Disease and 49 VascularDementia)- Diabetes increased the risk of dementia: -2,6 times for Vascular Dementia, and 1,3 times for Alzheimer Disease- Diabetes increased the risk of Dementia, in particular in very old people- The risk of Dementia was especially high when Diabetes occured together !with severe systolic hypertension or heart disease



Cognitive decline and glycemia

Brayne C, Neurobiol Aging 2005

Association with increased HbA1c and cognitive decline

HbA1c 3.7-5.2 5.3-5.7 5.8-6.9 >7 Self-reported DM

% 3.7 8.6 11.5 37 2.6

Risk for cognitive decline

1.0 2.3 3.6 11.2 1.0



Risk of Incident Dementia Associated withAverage Glucose Level over the Preceding 5 Years among People without Diabetes

Crane et al. N Engl J Med 2013



History of Medically Treated Diabetes and Risk of Alzheimer Disease ina Nationwide Case-Control Study in Finland

Tolppanen et al.Diabetes Care2013; 36:2015–29



Vantaa 85+ study - Finland

To investigate the association of diabetes with dementia and its main sub-types, Alzheimer disease and Vascular Dementia through analyses of incidence and neuropathological outcomes in a population-based study.


Adjusted HR= 2.45 (1.33-4.53)

0.00

0.10

0.20

0.30 C

umul

ativ

e in

cide

nce

0 1 2 3 4 5 6 7 8 9 10 Follow-up time, years non-DM DM

Alzheimer’s disease Adjusted HR= 2.15 (1.06-4.36)

0.00

0.10

0.20

0.30

Cum

ulat

ive

inci

denc

e

0 1 2 3 4 5 6 7 8 9 10 Follow-up time, years non-DM DM

Vascular dementia


Vantaa 85+ study: Incidence of Alzheimer Disease and VascularDementia by Diabetes in the Elderly Finns

Adjusted Risk with diabetes = 2.45

Adjusted Risk with diabetes = 2.15



Vantaa 85+ study: Autopsy population characteristics

• n=291- mean age at death: 92 (range 85-106) years - 84% female- 24% with diabetes- 65% with dementia at death- 31% with ApoE ε4

• Neuropathology: Same dissection and examination protocol were used for each brain following the CERAD protocol (Polvikoski et al., NEJM 1995, Neurology 2001)



Vantaa 85+ study: Diabetes & cerebral infarcts

0

25

50

75

100

No DM ( N=192) DM ( N=62)

Proportion of subjects with cerebral infarcts Diabetes and Risk for cerebral infarcts

44.4 61.3

0

0.5

1

1.5

2

No DM ( N=192) Model1 Model2

1.92 1.79

No Cerebral infarctsCerebral infarcts Model 1: adjusted for age at death and gender.

Model 2: Model 1 + education, ApoE ε4, dementia

p=0.028



Vantaa 85+ study: Diabetes & ß-amyloid

0

25

50

75

100

No DM ( N=226) DM ( N=65)

Proportion of subjects with β-amyloid Diabetes and OR (95%CI) for β-amyloid

86.7 72.3

0

0.25

0.5

0.75

1

No DM Model1 Model2Model 1: adjusted for age at death and gender. Model 2: Model 1 + education, ApoE ε4, dementia

0.37 0.33No Amyloid Amyloid

p=0.008



Vantaa 85+ study: Diabetes & tangles

0

37.5

75

112.5

150

No DM ( N=221) DM ( N=62 )

Proportion of subjects with tangles Diabetes and OR (95%CI) for tangles

67 56.5

0

0.25

0.5

0.75

1

No DM Model1 Model2Model 1: adjusted for age at death and gender. Model 2: Model 1 + education, ApoE ε4, dementia

0.65 0.6No Tangles Tangles

p=0.14



Possible etiology of cognitive decline in Diabetes

• Cognitive decline due to cerebrovascular disease• Insulin resistance

- high peripheral insulin, low cerebral insulin- Disturbed glucose transport- Endothelial dysfunction- Beta-Amyloid accumulation ?

• Hyperglycemia- Direct neurotoxic effect- Endothelial dysfunction

• Hypoglycemia (treated patients)- “Fuel deprivation”

• Inflammation?



Possible mechanisms

Xu WL modified based on Biessels GJ et al. 2006 and Launer LJ. 2005

Brain pathology

• Comorbidity• Medication

Genetic predisposition

Diabetes

“Accelerated aging"

Microvascular Disease

•Insidious ischaemia

Glucose toxicity•Advanced protein glycation• Oxidative stress• Inflammation

Alzheimer type

Insulin↑β-amyloid

↑Phosphorylation of tau

Insulin

Underlying mechanisms

Dementia

Vascular

Atherosclerosis

•Brain infarcts

Insulin↑β-amyloid

↑Phosphorylation of tau

Insulin



Finnish Diabetes Prevention Study (DPS): lifestyle goals

• Weight reduction > 5%• Fat intake < 30 E% • Saturated fat intake < 10 E% • Fibre intake ≥ 15 g/1000 kcal• Physical activity > 30 min/day

Intervention group

• Individually tailored diet based on 3-day food diary• 7 dietary counselling sessions during the first year, every 3 months thereafter• Free-of-charge gym

Tuomilehto et al. NEJM 2001 Lindström et al. Diabetes Care 2003

Control group

• General advice about healthy diet and exercise habits• No individualized counseling

E, energy



Development of diabetes during the lifestyle intervention in the intervention and control groups - DPS

00.10.20.30.40.50.60.70.80.9

1

0 1 2 3 4 5 6

Intervention Group Control Group

Risk reduction: 58%



Prevention of Type 2 Diabetes by Lifestyle Management: The Evidence

DPS - Finland DPP - USA SLIM - Netherlands

0

10

20

30

40

50

0 1 2 3 4 5 6

YEAR

Intervention group Control Group

EDIPS Newcastle - UK Da Qing - China IDPP - India

Risk 58% ↓ Risk 58% ↓ Risk 58% ↓

Risk 58% ↓ Risk 43% ↓ Risk 28.5% ↓

Lifestyle

Control

Metformin



Development of diabetes is inversely related to the success in achieving multiple intervention targets

during the 1st year of the study - DPS

0

7

13

20

27

33

40

0 1 2 3 4 5

InterventionControl

%



Unadjusted Adjusted for baseline weight, group and sex

RELATIVE RISK for diabetes according to weight change from baseline to year 1: DPS

00.20.40.60.81.01.21.41.61.82.0

0 1 2 3 4


Dr. Jaakko TuomilehtoMonday, September 16, 13

HEALTHYDIET

MODEL 1 MODEL 2 MODEL 3

DementiaLow adherence (0-8 points)High adherence (>8 points)

86% 90% 88%

Alzheimer’sLow adherence (0-8 points)High adherence (>8 points)

90% 92% 92%


Association between healthy diet and Alzheimer's among participants



THANK YOU


diabetes prevention studies and implications for alzheimer research | dr. jaakko toumilehto

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