1. “ The 10/66 Dementia Research Group Studies”. Incidence phase. Incidence phase. Juan J. Llibre Rodriguez. For and on behalf of 10/66 26 th International Conference of Alzheimer’s Disease International.

2. INCIDENCE RATES Burden of a disease. Risk of disease I x duration = Prevalence I x case fatality = Burden of mortality Predict future cases Planning health services Evaluate the impact of prevention Study risk factors.

3. Incidence phase (n=13,000) Sites –Cuba, DR, Venezuela, Mexico, Peru, China Outcomes –Dementia, Stroke, Dependence, Mortality Aetiology Cardiovascular risk (BP/ smoking/ fasting glucose/ cholesterol) Diet (anaemia, B12, folate, subclinical hypothyrodism, albumin, anthropometry) Developmental factors APOE and other genetic factors

4. Incidence wave, by country CountryCohortInter- viewed DeadLost to follow-up Median follow-up (years) Person years (dementia) Cuba281320076081984.58701 DR201111974673475.15561 Peru193313111524703.33914 Venezuela196512572005084.35269 Mexico200314622093323.04164 China216214525151955.17109 Total1288781372151205034718 Total (%)69%17%16%

5. Mortality in dementia

6. Mortality among people with dementia, by site SiteMortality rate (per 1000 person years) Age and sex adjusted mortality hazard ratios No dementia Dementia cases Cuba44.8195.43.20 (2.61-3.92) Dominican Republic54.5148.32.22 (1.75-2.81) Peru, urban18.7139.35.69 (3.33-9.73) Peru, rural28.959.51.74 (0.68-4.44) Venezuela24.398.42.27 (1.42-3.62) Mexico, urban31.6114.42.70 (1.56-4.67) Mexico, rural36.689.71.56 (0.94-2.59) China, urban40.7168.13.02 (2.13-4.28) China, rural57.0216.13.59 (2.47-5.21) India, urban62.5171.62.33 (1.48-3.67) Pooled meta-analysed effect 2.77 (2.47-3.10)

7. Factors tested as possible predictors of mortality, among people with dementia Sociodemographic factors AgeAssets GenderIn receipt of pension EducationHealth insurance Dementia related factors Cognitive function (COGSCORE)Dementia severity (CDR) Dementia subtypeBehavioural symptoms General health factors Previous strokePhysical illness Disability (WHODAS 2.0 score)Undernutrition (arm circumference) Depression Care-related factors Number of co-residentsNeeds for care Co-resident childCo-resident spouse

8. Predictors of mortality (stepwise regression), among people with dementia PredictorHazard ratio for mortality (95% CI) P-value Sociodemographic factors Age (per 5 year band)1.29 (1.16-1.44)<0.001 Male gender1.92 (1.55-2.39)<0.001 Dementia related factors Cognitive function (COGSCORE)0.98 (0.97-0.99)0.001 Frontotemporal dementia type0.45 (0.23-0.88)0.02 General health factors Previous stroke0.76 (0.59-0.98)0.03 Disability (WHODAS 2.0 score)1.01 (1.01-1.02)<0.001 Undernutrition (arm circumference)1.30 (1.02-1.66)0.03 Care-related factors Number of co-residents1.05 (1.00-1.11)0.06 Co-resident child0.82 (0.72-0.93)0.02 Co-resident spouse0.74 (0.59-0.92)0.008

9. Carer strain

10. Changes in carer strain since baseline

11. Factors tested as possible predictors of carer strain at follow-up Sociodemographic factors AgeEducation GenderFollow-up interval Dementia related factors Change in cognitive functionDementia severity (CDR) Dementia subtypeBehavioural symptoms Quality of life at follow-up (DEMQOL) General health factors Previous strokePhysical illness Disability (WHODAS 2.0 score)Depression Care-related factors AgeNumber of co-residents GenderCo-resident child Needs for careCo-resident spouse

12. Predictors of carer strain (stepwise regression), among people with dementia PredictorRegression coefficient (95% CI) P-value Sociodemographic factors Follow-up period (per year)+1.9 (-0.2 to +4.0)0.07 Dementia related factors Change in cognitive function (per one point decline in COGSCORE) +0.4 (+0.2 to +0.6)<0.001 Behavioural symptoms+0.4 (+0.1 to +0.6)0.008 Frontotemporal dementia type-9.5 (-16.4 to -2.6)0.007 Quality of life at follow-up-0.2 (-0.3 to -0.1)0.004 General health factors ICD-10 depressive episode-4.9 (-9.4 to -0.4)0.03 Disability (WHODAS 2.0 score)+0.1 (+0.0 to +0.1)0.03 Care-related factors Needs for care+6.3 (+2.0 to +10.5)0.004 Carer age+0.1 (+0.0 to +0.2)0.02

13. DSM-IV dementia * 10/66 Dementia Any dementia ALL 9.0021.0421.17 BY SEX Male 9.3918.36 Female 8.8022.4122.60 BY AGE 65-69 3.275.95 70-74 8.9718.1818.61 75-79 11.6727.64 80+ 16.2948.85 * Incidence rate/ 1000 pyr Incidence of dementia by sex and age, Cuba Cohort 65 years and over N=2728

14. Risk factors for incident dementia Age group 1.79 (1.37-2.37) Male gender 1.27 (0.62-2.60) Education level 0.79 (0.67-0.98) Leg length 1.02 (0.98-1.06) Skull circ 1.06 (0.91-1.23) Smoker 0.77 (0.40-1.48) Hypertension 1.35 (1.02-2.37) Parkinsonism score 1.18 (1.05-1.33) Fish Frequency 0.40 (0.22-0.74) Hazardous drinker 1.66 (0.54-5.06) Stroke 2.84 (1.20-6.72) APOE 4 2.01 (1.03-3.92) FH Dementia 1.39 (0.72-2.64)

15. Population 11,6 millons Life expectancy Men 79 years Women 80 years Dementia´s prevalence 6.4-10.2 % (130 000 cases ) Incidence rate 21.7 per 1000/year (28 760 new cases/year) Mortality rate in dementia people 195.5 per 1000/year

16. Does African ancestry protect against dementia? A population-based case-control study in an admixed Cuban population? Admixtures mapping provides information about the contribution of genetic and non genetic factors. In Cuba, there is sufficient variation of admixture between individuals to detect relationships of disease risk to proportionate admixture.

17. 10/66 admixture studies Design –Populations of mixed African and Caucasian ancestry –Genotype to measure ancestry directly in individuals Hypothesis –Higher levels of African ancestry associated with lower risk of dementia

18. Main source of admixture Migration, 1400–1800,

19. Cuba – association of APOE genotype with dementiaDementia N 273 (%) No dementia N 2247 (%) Crude PR (95% CI) Adj. PR (95% CI)* 1 or 2 alleles ApoE4 87 (31.9) 329 (14.6) 2.4 (1.9-3.0) 2.6 (2.1-3.2) Number of ApoE4 alelles 0 186 (68.1) 1918 (85.4) 1.00 (ref.) 1 79 (28.9) 300 (13.4) 2.35 (1.9- 3.0) 2.6 (2.0-3.2) 2 8 (2.9) 29 (1.3) 2.45 (1.3- 4.6) 2.9 (1.6-5.3) * Adjusted age, sex and education

20. APOE allele frequency White n=1677 (72%)Mixedn=394(17%)Blackn=261(11%) P-value test for trend E20.0570.064 0.072 0.072<0.001 E30.865 0.852 0.8520.780 E40.078 0.084 0.0840.148 Association between any E4 and dementia 2.84(2.2-3.6)0.81(0.2-2.8)2.38(1.4-3.9) Overall association between E4 and any dementia 2.58 (2.06- 3.22) Adjusted for race2.50(1.91-3.21) APOE allele frequency by ethno-racial identity

21. Mean admixture proportion by APOE allele status (case control subsample) APOE genotype Admixture proportions No APOE allele N= 445 One APOE allele N=119 Two APOE allele N=20 P value African mean 95% CI 0.15(0.13-0.18)0.19 (0.15 - 0.23) 0.35(0.22-0.48) P = 0.01 European mean 95% CI 0.82(0.80-0.84) 0.78 0.78(0.74-0.83)0.62(0.48-0.75) P = 0.007 Native american 0.03(0.02-0.03)0.03(0.02-0.04)0.03(0.02-0.05) P = 0.65 *

22. Incidence of dementia according age group and APOE 4 genotype (HR). Cuba 10/66 incidence phase. Age group 1 or 2 APOE4 allele No APOE4 allele 65-69 6.56 (2.16-19.9) 3.67 70-74 3.34 (1.82-6.14) 1.87 75-79 5.74 (3.91 10.5) 3.21 80+ 11.3 (5.97-21.5) 6.34 Interaction term 0.56 (0.37-0.85) * p<0.006

23. Conclusions The world is facing a new epidemic of unprecedented proportions Its effects will be felt particularly in low and middle income countries - currently least prepared to meet the challenge Societal costs will rise inexorably, driven by the increasing need for long term care Time for action –Clinical care –Social policy –Prevention

24. The next steps Care/ Impact Care/ Impact – Intervention! Incidence phase I (2006-2010) II (2010 -2014) Incidence phase I (2006-2010) II (2010 -2014) –Aetiology Cardiovascular risk (BP/ smoking/ fasting glucose/ cholesterol) Cardiovascular risk (BP/ smoking/ fasting glucose/ cholesterol) Diet (anaemia, B12, folate, subclinical hypothyrodism, albumin, anthropometry) Diet (anaemia, B12, folate, subclinical hypothyrodism, albumin, anthropometry) Developmental factors Developmental factors APOE effect modification APOE effect modification African ancestry African ancestry –Chronic non communicabke diseases

26. 10/66 Dementia Research Group 10/66 Dementia Research Group www.alz.co.uk/1066