“ “ The 10/66 Dementia Research Group Studies”The 10/66 Dementia Research Group Studies”. . Incidence phase.Incidence phase. Juan J. Llibre Rodriguez. For and on behalf of 10/66

2626thth International Conference of Alzheimer’s International Conference of Alzheimer’s Disease International. Disease International.

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.

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

Incidence wave, by country

Country Cohort Inter-viewed

Dead Lost to follow-up

Median follow-up (years)

Person years (dementia)

Cuba 2813 2007 608 198 4.5 8701DR 2011 1197 467 347 5.1 5561Peru 1933 1311 152 470 3.3 3914Venezuela 1965 1257 200 508 4.3 5269Mexico 2003 1462 209 332 3.0 4164China 2162 1452 515 195 5.1 7109Total 12887 8137 2151 2050 34718Total (%) 69% 17% 16%

Mortality in dementia

Mortality among people with dementia, by site

Site Mortality rate (per 1000 person years)

Age and sex adjusted mortality hazard ratiosNo

dementiaDementia cases

Cuba 44.8 195.4 3.20 (2.61-3.92)Dominican Republic 54.5 148.3 2.22 (1.75-2.81)Peru, urban 18.7 139.3 5.69 (3.33-9.73)Peru, rural 28.9 59.5 1.74 (0.68-4.44)Venezuela 24.3 98.4 2.27 (1.42-3.62)Mexico, urban 31.6 114.4 2.70 (1.56-4.67)Mexico, rural 36.6 89.7 1.56 (0.94-2.59)China, urban 40.7 168.1 3.02 (2.13-4.28)China, rural 57.0 216.1 3.59 (2.47-5.21)India, urban 62.5 171.6 2.33 (1.48-3.67)

Pooled meta-analysed effect

2.77 (2.47-3.10)

Factors tested as possible predictors of mortality, among people with dementia

Sociodemographic factors

Age Assets

Gender In receipt of pension

Education Health insurance

Dementia related factors

Cognitive function (COGSCORE) Dementia severity (CDR)

Dementia subtype Behavioural symptomsGeneral health factorsPrevious stroke Physical illnessDisability (WHODAS 2.0 score) Undernutrition (arm circumference)DepressionCare-related factorsNumber of co-residents Needs for careCo-resident child Co-resident spouse

Predictors of mortality (stepwise regression), among people with dementia

Predictor Hazard ratio for mortality (95% CI)

P-value

Sociodemographic factors

Age (per 5 year band) 1.29 (1.16-1.44) <0.001

Male gender 1.92 (1.55-2.39) <0.001

Dementia related factors

Cognitive function (COGSCORE) 0.98 (0.97-0.99) 0.001

Frontotemporal dementia type 0.45 (0.23-0.88) 0.02General health factorsPrevious stroke 0.76 (0.59-0.98) 0.03Disability (WHODAS 2.0 score) 1.01 (1.01-1.02) <0.001Undernutrition (arm circumference) 1.30 (1.02-1.66) 0.03Care-related factorsNumber of co-residents 1.05 (1.00-1.11) 0.06Co-resident child 0.82 (0.72-0.93) 0.02Co-resident spouse 0.74 (0.59-0.92) 0.008

Carer strain

Changes in carer strain since baseline

Factors tested as possible predictors of carer strain at follow-up

Sociodemographic factors

Age Education

Gender Follow-up interval

Dementia related factors

Change in cognitive function Dementia severity (CDR)

Dementia subtype Behavioural symptomsQuality of life at follow-up (DEMQOL)General health factorsPrevious stroke Physical illnessDisability (WHODAS 2.0 score) DepressionCare-related factorsAge Number of co-residentsGender Co-resident childNeeds for care Co-resident spouse

Predictors of carer strain (stepwise regression), among people with dementia

Predictor Regression 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) 0.008Frontotemporal dementia type -9.5 (-16.4 to -2.6) 0.007Quality of life at follow-up -0.2 (-0.3 to -0.1) 0.004General health factorsICD-10 depressive episode -4.9 (-9.4 to -0.4) 0.03Disability (WHODAS 2.0 score) +0.1 (+0.0 to +0.1) 0.03Care-related factorsNeeds for care +6.3 (+2.0 to +10.5) 0.004Carer age +0.1 (+0.0 to +0.2) 0.02

DSM-IV dementia *

10/66 Dementia

Any dementia

ALL 9.00 21.04 21.17BY SEXMale 9.39 18.36 18.36Female 8.80 22.41 22.60BY AGE65-69 3.27 5.95 5.9570-74 8.97 18.18 18.6175-79 11.67 27.64 27.6480+ 16.29 48.85 48.85

* Incidence rate/ 1000 pyr

Incidence of dementia by sex and age, Cuba Cohort 65 years and over N=2728

Risk factors for incident dementiaRisk factors for incident dementiaAge groupAge group 1.79 (1.37-2.37)1.79 (1.37-2.37)Male genderMale gender 1.27 (0.62-2.60)1.27 (0.62-2.60)Education levelEducation level 0.79 (0.67-0.98)0.79 (0.67-0.98)Leg lengthLeg length 1.02 (0.98-1.06)1.02 (0.98-1.06)Skull circSkull circ 1.06 (0.91-1.23)1.06 (0.91-1.23)SmokerSmoker 0.77 (0.40-1.48)0.77 (0.40-1.48)HypertensionHypertension 1.35 (1.02-2.37)1.35 (1.02-2.37)Parkinsonism scoreParkinsonism score 1.18 (1.05-1.33)1.18 (1.05-1.33)Fish FrequencyFish Frequency 0.40 (0.22-0.74)0.40 (0.22-0.74)Hazardous drinkerHazardous drinker 1.66 (0.54-5.06)1.66 (0.54-5.06)StrokeStroke 2.84 (1.20-6.72)2.84 (1.20-6.72)APOE 4APOE 4 2.01 (1.03-3.92)2.01 (1.03-3.92)FH DementiaFH Dementia 1.39 (0.72-2.64)1.39 (0.72-2.64)

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

Does African ancestry Does African ancestry protect against dementia? A protect against dementia? A population-based case-population-based case-control study in an admixed control study in an admixed Cuban populationCuban population??

Admixtures Admixtures mapping provides mapping provides information about the contribution of information about the contribution of

genetic and non genetic factors.genetic and non genetic factors.In Cuba, there is sufficient variation of In Cuba, there is sufficient variation of

admixture between individuals to admixture between individuals to detect relationships of disease risk to detect relationships of disease risk to

proportionate admixture.proportionate admixture.

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

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

  

Cuba – association of APOE genotype with dementia

DementiDementiaaN 273 (%)N 273 (%)

No No dementidementiaaN 2247 N 2247 (%)(%)

Crude PR Crude PR (95% CI)(95% CI)

Adj. PR Adj. PR (95% CI)(95% CI)**

1 or 2 1 or 2 alleles alleles ApoE4ApoE4

87 (31.9)87 (31.9) 329 (14.6)329 (14.6) 2.4 (1.9-3.0)2.4 (1.9-3.0) 2.6 (2.1-3.2)2.6 (2.1-3.2)

Number of ApoE4 alellesNumber of ApoE4 alelles00 186 (68.1)186 (68.1) 1918 (85.4)1918 (85.4) 1.00 (ref.)1.00 (ref.) 1.00 (ref.)1.00 (ref.)11 79 (28.9)79 (28.9) 300 (13.4)300 (13.4) 2.35 (1.9-2.35 (1.9-

3.0)3.0)2.6 (2.0-3.2)2.6 (2.0-3.2)

22 8 (2.9)8 (2.9) 29 (1.3)29 (1.3) 2.45 (1.3-2.45 (1.3-4.6)4.6)

2.9 (1.6-5.3)2.9 (1.6-5.3)* * Adjusted age, sex and educationAdjusted age, sex and education

APOE allele APOE allele frequencyfrequency

White White n=1677n=1677(72%) (72%)

MixedMixed n=394n=394(17%) (17%)

BlackBlack n=261n=261 (11%) (11%)

P-valueP-value test for test for trendtrend

E2 E2 0.0570.057 0.064 0.064 0.0720.072 <0.001<0.001E3E3 0.8650.865 0.8520.852 0.7800.780 E4E4 0.0780.078 0.0840.084 0.1480.148 Association Association between any E4 between any E4 and dementiaand dementia

2.84 2.84 (2.2-3.6)(2.2-3.6)

0.810.81(0.2-2.8)(0.2-2.8)

2.38 2.38 (1.4-3.9)(1.4-3.9)

Overall association Overall association between E4 and between E4 and any dementiaany dementia

2.58 2.58 (2.06- 3.22)(2.06- 3.22)

Adjusted for race 2.50 2.50 (1.91-3.21)(1.91-3.21)

APOE allele frequency by ethno-racial identity

  

Mean admixture proportion by APOE allele status (case control subsample)

APOE APOE genotype genotype Admixture Admixture proportionsproportions

No APOE No APOE allelealleleN= 445N= 445

One APOE One APOE allelealleleN=119N=119

Two APOE Two APOE allelealleleN=20N=20

P valueP value

African mean African mean 95% CI95% CI

0.150.15(0.13-(0.13-0.18)0.18)

0.19 0.19 (0.15 - (0.15 - 0.23)0.23)

0.35 0.35 (0.22-(0.22-0.48)0.48)

P = 0.01P = 0.01

European European mean 95% CImean 95% CI

0.82 0.82 (0.80-(0.80-0.84)0.84)

0.780.78(0.74-0.83)(0.74-0.83)

0.620.62(0.48-(0.48-0.75)0.75)

P = 0.007P = 0.007

Native Native american american

0.03 0.03 (0.02-(0.02-0.03)0.03)

0.03 0.03 (0.02-0.04)(0.02-0.04)

0.03 0.03 (0.02-(0.02-0.05)0.05)

P = 0.65P = 0.65

* *

  

Incidence of dementia according age group and APOE 4 genotype (HR). Cuba 10/66 incidence

phase.Age groupAge group 1 or 2 APOE4 1 or 2 APOE4

allelealleleNo APOE4 alleleNo APOE4 allele

65-6965-69 6.56 (2.16-19.9)6.56 (2.16-19.9) 3.673.67

70-7470-74 3.34 (1.82-3.34 (1.82-6.14)6.14)

1.871.87

75-7975-79 5.74 (3.91 5.74 (3.91 10.5)10.5)

3.213.21

80+80+ 11.3 (5.97-11.3 (5.97-21.5)21.5)

6.346.34

Interaction termInteraction term 0.56 (0.37-0.56 (0.37-0.85)0.85)

**p<0.006p<0.006

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

The next steps

• Care/ ImpactCare/ Impact– Intervention! Intervention!

• Incidence phase I (2006-2010) Incidence phase I (2006-2010) II (2010 -2014)II (2010 -2014)– AetiologyAetiology

• Cardiovascular risk (BP/ smoking/ fasting glucose/ Cardiovascular risk (BP/ smoking/ fasting glucose/ cholesterol)cholesterol)

• Diet (anaemia, B12, folate, subclinical hypothyrodism, Diet (anaemia, B12, folate, subclinical hypothyrodism, albumin, anthropometry)albumin, anthropometry)

• Developmental factorsDevelopmental factors• APOE effect modification APOE effect modification • African ancestryAfrican ancestry

– Chronic non communicabke diseasesChronic non communicabke diseases

•

10/66 Dementia Research Group10/66 Dementia Research Group

www.alz.co.uk/1066