Cognitive ageing and dementia: The Whitehall II Study

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1 Cognitive ageing and dementia: The Whitehall II Study Archana SINGH-MANOUX NIH: R01AG013196; R01AG034454; R01AG MRC: K013351, MR/R BHF: RG/13/2/30098 H2020: # #633666

2 Outline Lifecourse approach: relevance for cognitive age & dementia Cognitive ageing: our results Dementia: our approach & recent results Separate risk from bias (midlife risk) Reverse causation

3 Why the lifecourse approach? Increasing life expectancy, increase in numbers living with dementia 47 million in 2015, 131 million in the year year delay in dementia onset will lead to 9.2 million fewer cases by 2050 Failure rate of drugs 100% Failure of multi-domain trials (Multidomain Alzheimer Preventive Trial, MAPT)

4 Why the lifecourse approach? Considerable investment in imaging studies (MRI, CSF), etc. but correlation between brain structure and function far from perfect Nelson et al., J Neuropathol Exp Neurol 2009

5 Major studies on ageing start data collection at age 65 Study Country Start N Age Iceland Birth Cohort Study Iceland Gothenburg Study Sweden PAQUID France Kungsholmen Project Sweden Rotterdam Netherlands Cognitive Function & Ageing Study (CFAS) UK Etude du Vieillissement Artériel (EVA) France Italian Longitudinal Study on Aging (ILSA) Italy Longitudinal Aging Study Amsterdam (LASA) Netherlands Maastricht Aging Study (MAAS) Netherlands Longitudinal Study of Aging Danish Twins Denmark The German Aging Survey Germany In Chianti Study Italy City Study France The Swedish National study of Aging & Care Sweden Newcastle 85+ Study UK UK Biobank UK 2006/ , CONSTANCES France 2012/ , Visiting Committee HCERES February 2018 NAKO Germany 2014/ ,

6 Cognitive function over the lifecourse

7 Cognitive function over the lifecourse: WHY? PLASTICITY! enhance reserve Delay decline Modify rate of decline Identify (unbiased) risk factors Function 20 years 65 years Disability Dementia

8 The Whitehall study: unique data to study ageing outcomes DATA COLLECTION 2018/20 8

9 Our approach: cognitive ageing and dementia Genetic factors Environment Socioeconomic Psychosocial Health behaviours Cardiovascular Metabolic Inflammatory Heterogeneity in cognitive decline DEMENTIA Mortality continuum from function to pathology

10 No cognitive decline before age 60? Results from the Seattle Longitudinal Study Hedden et al. Nat Rev Neurosci. 2004

11 No cognitive decline before age 60? Results from the Seattle Longitudinal Study Results from the Whitehall II Study Hedden et al. Nat Rev Neurosci Singh-Manoux et al. BMJ 2012 baseline MEN WOMEN N=5198 N= yrs yrs yrs yrs yrs

12 Smoking history and cognitive decline Sabia, Singh-Manoux. JAMA Psychiatry Mixed model - Current smokers Joint models - Current smokers

13 Cardiovascular risk & cognitive ageing Framingham risk scores & decline in global cognitive score Kaffashian, Singh-Manoux. Eur Heart J 2011 Kaffashian, Singh-Manoux. Neurology 2013 Kaffashian, Singh-Manoux. Alzheimers Dement 2013

14 Cardiovascular risk & cognitive ageing Framingham risk scores & decline in global cognitive score Atrial fibrillation & cognitive decline Kaffashian, Singh-Manoux. Eur Heart J 2011 Singh-Manoux et al., Eur Heart J 2017 Kaffashian, Singh-Manoux. Neurology 2013 Kaffashian, Singh-Manoux. Alzheimers Dement 2013

15 Our approach to research on dementia

16 The Whitehall Study Dementia: our approach & recent results Separate risk from bias (midlife risk) Reverse causation EHR data for dementia are good enough!

17 BMI and dementia year of dementia diagnosis Singh-Manoux et al., Alzheimers Dement. 2018

18 BMI and dementia HR (95%CI) BMI (Kg/m 2 ) at 50 years < ( ) ( ) ( ) BMI (Kg/m 2 ) at 60 years < 18.5 NA ( ) ( ) BMI (Kg/m 2 ) at 70 years < ( ) ( ) ( ) year of dementia diagnosis Singh-Manoux et al., Alzheimers Dement. 2018

19 Hypertension & dementia Hypertension: systolic blood pressure threshold 50 years 60 years 70 years Abell, Singh-Manoux, Eur Heart J. 2018

20 Hypertension & dementia: effet of age Analysis adjusted for age, sex, education, ethnicity, marital status, occupational position, health behavours, BMI, diabetes, cardiovascular disease (coronary heart disease, stroke). Abell, Singh-Manoux, Eur Heart J. 2018

21 Hypertension & dementia: role of CVD 50 years HR= % CI: 1.27, 1.53 Cardiovascular disease HR= % CI: 0.95, 2.08 Analysis adjusted for age, sex, education, ethnicity, marital status, occupational position, health behavours, BMI, diabetes, cardiovascular disease (coronary heart disease, stroke). HR= % CI: 1.07, 1.90 Incident Dementia Abell, Singh-Manoux, Eur Heart J. 2018

22 Reverse causation Physical activity Meta-analysis of observational studies suggest an association Blondelet al. BMC Public Health 2014 Intervention studies: null findings Sink et al. JAMA 2015 Andrieu et al. Lancet Neurol 2017 Depressive symptoms Meta-analysis of observational studies suggest an association Ownby et al. Arch Gen Psychiatry For both exposures, evidence of stronger associations in studies with a short follow-up

23 Physical activity Meta-analysis of observational studies suggest an association Blondelet al. BMC Public Health 2014 Intervention studies: null findings Sink et al. JAMA 2015 Andrieu et al. Lancet Neurol 2017 Depressive symptoms Meta-analysis of observational studies suggest an association Ownby et al. Arch Gen Psychiatry For both exposures, evidence of stronger associations in studies with a short follow-up

24 Trajectories of total physical activity (hours/week) prior to dementia Total physical activity(hours/week) P for difference in trajectories: < Years prior to dementia diagnosis Years Dementia free (N=9979) Dementia cases (N=329) -28 to to -20 Number of observations in the analysis -20 to to to -8-8 to -4-4 to Sabia, Singh-Manoux BMJ 2017

25 Trajectories of physical activity prior to dementia Total physical activity Diff in trajectory, p< Mild physical activity Diff in trajectory, p< Moderate & vigorous physical activity Diff in trajectory, p=0.001 Total physical activity(hours/week) Years prior to dementia diagnosis Mild physical activity(hours/week) Years prior to dementia diagnosis MVPA(hours/week) Years prior to dementia diagnosis Mixed models adjusted for 5y birth cohort, age at time 0, sex, ethnicity, education, dementia, time, time², time 3, their interactions with time, time², time 3, time-dependent covariates socio-economic and behavioural variables Sabia, Singh-Manoux BMJ 2017

26 Trajectories of depressive syndromes prior to dementia Singh-Manoux et al. JAMA Psychiatry 2017

27 Conclusions Risk factors for dementia Which ones? Age of exposure (timing & duration) Threshold of risk Prevention Failure of drug trials How do risk factors work together? When does prevention begin? the vascular system is a phenomenal target because we have in our brains about 400 miles of blood vessels and these have to do their primary job of bringing food and oxygen to the brain and taking toxins out of the brain. Zlokovic, JAMA 2017

28 Thank you! 28

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