Diabetes prevention studies and implications for Alzheimer research | Dr. Jaakko Toumilehto

Dr. Jaakko Tuomilehto
Professor 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

0
7.5
15
22.5
30
PrevalenceofDiabetes(%)
1.1 2.7
5.7
9
12.8
11.8
1.5
1.9 5.1
9.5
14.5
21.5
30 - 39
40 - 49
50 - 59
60 - 69
70 - 79
80 - 89
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., 1995
Leibson et al., 1997
Brayne et al., 1998
Ott et al., 1999
Peila et al., 2002
Yamada et al 2003
Arvanitakis et al., 2004
Luchsinger et al., 2005
Akomolafe et al., 2006
Irie et al., 2008
Xu et al. 2009
Ahtiluoto et al. 2010
No association:
Curb et al., 1999
MacKnight et al,. 2002
Hassing et al., 2002
Xu et al., 2004
Hayden 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 years
Estimation 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 with
Average 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 in
a 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
0.30Cumulativeincidence
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
Cumulativeincidence
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 infarcts
Cerebral 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 Model2
Model 1: adjusted for age at death and gender.
0.37 0.33
No 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 Model2
Model 1: adjusted for age at death and gender.
0.65 0.6
No 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
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
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
Intervention
Control
%

Unadjusted Adjusted for baseline weight, group and sex
RELATIVE RISK for diabetes according to
weight change from baseline to year 1: DPS
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
0 1 2 3 4

HEALTHY
DIET
MODEL 1 MODEL 2 MODEL 3
Dementia
Low adherence (0-8 points)
High adherence (>8 points)
86% 90% 88%
Alzheimer’s
Low 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

Diabetes prevention studies and implications for Alzheimer research | Dr. Jaakko Toumilehto

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