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

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Dr. Jaakko Toumilehto, Professor of Public Health at the University of Helsinki, Finland. He is also affiliated with the Diabetes and Genetic Epidemiology Unit of the ...

Dr. Jaakko Toumilehto, Professor of Public Health at the University of Helsinki, Finland. He is also affiliated with the Diabetes and Genetic Epidemiology Unit of the
National Public Health Institute in Helsinki, Finland, and holds positions as Professor at the Danube-University Krems, Austria. Dr. Jaakko has published over 800 peer-reviewed original articles and an estimated 200 editorials, reviews and book chapters.

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

    • 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 Dr. Jaakko Tuomilehto Monday, September 16, 13
    • 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 Dr. Jaakko Tuomilehto Prevalence of known diabetes (%) in Europe by age-group, DECODE Male Female Monday, September 16, 13
    • Dr. Jaakko Tuomilehto The International Diabetes Federation Diabetes Atlas 5th Edition A summary of the figures and key findings Monday, September 16, 13
    • Dr. Jaakko Tuomilehto Diabetes: the Top 10s (prevalence, % of the population) Monday, September 16, 13
    • Dr. Jaakko Tuomilehto Diabetes: Regional overview and projections Monday, September 16, 13
    • • 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 Dr. Jaakko Tuomilehto Diabetes: the global burden Monday, September 16, 13
    • Dr. Jaakko Tuomilehto Undiagnosed diabetes Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 ? ? Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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) Monday, September 16, 13
    • Dr. Jaakko Tuomilehto Diabetes Mellitus increases the risk of Dementia (2) 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) Monday, September 16, 13
    • Dr. Jaakko Tuomilehto Diabetes Mellitus increases the risk of Dementia (4) 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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. Monday, September 16, 13
    • 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 Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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) Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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. Model 2: Model 1 + education, ApoE ε4, dementia 0.37 0.33 No Amyloid Amyloid p=0.008 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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. Model 2: Model 1 + education, ApoE ε4, dementia 0.65 0.6 No Tangles Tangles p=0.14 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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? Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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% Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 % Monday, September 16, 13
    • Dr. Jaakko Tuomilehto 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 Monday, September 16, 13
    • Dr. Jaakko Tuomilehto Monday, September 16, 13
    • Dr. Jaakko Tuomilehto Monday, September 16, 13
    • 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% Dr. Jaakko Tuomilehto Association between healthy diet and Alzheimer's among participants Monday, September 16, 13
    • Dr. Jaakko Tuomilehto THANK YOU Monday, September 16, 13