““Does African ancestry protect against Does African ancestry protect against dementia? A population-based case-control study dementia? A population-based case-control study in an admixed Cuban populationin an admixed Cuban population? ? ..””

Juan J. Llibre Rodriguez , Beatriz Macheco Teruel , Cleusa Ferris, Paul McKeigue, Martin J Prince. For and on behalf of 10/66

Univ. de Ciencias Medicas - Habana, CubaUniv. de Ciencias Medicas - Habana, CubaCentro Nacional de Genetica, Havana,CubaCentro Nacional de Genetica, Havana,CubaCentre for Public Mental Health, KCL, UKCentre for Public Mental Health, KCL, UK

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 information about the

contribution of genetic and contribution of genetic and non genetic factors.non genetic factors.

In Cuba, there is sufficient In Cuba, there is sufficient variation of admixture variation of admixture

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

proportionate admixture.proportionate admixture.

The US/ Nigeria study

• Clear association between apoE e4 and AD in African Americans in Indianapolis, US

» (Hendrie - Ann Neurol 1995)

• No association between apoE e4 and AD in Yoruba in Ibadan, Nigeria

» (Osontokun - Ann Neurol 1995)

Prevalence of dementia by age in Prevalence of dementia by age in CubaCuba

0

5

10

15

20

25

30

65-69 70-74 75-79 80+

Age (years)

Prev. (%)

Cuba - 10/66

Cuba - DSM IV

EURODEM

Llibre Rodríguez J.J, Valhuerdi A., Sanchez I.I., Guerra M.A, Prince M, et al. “The prevalence, correlates and impact of dementia in Cuba”. Neuroepidemiology 2008;31:243–251.

DSM-IV dementia *

10/66 Dementia

Any dementia

ALL 9.00 21.04 21.17

BY SEX

Male 9.39 18.36 18.36

Female 8.80 22.41 22.60

BY AGE

65-69 3.27 5.95 5.95

70-74 8.97 18.18 18.61

75-79 11.67 27.64 27.64

80+ 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 dementia

Age 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)

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

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

Esperanza

Aged 104 years!

•Door knocking

•Cognitive test

• Clinical interview

• Socio-demographic and risk factor interview

• Physical/ neurological examination

• Blood test

• Informant interview

10/66 Dementia diagnosisDSM IV DementiaDSM IV/ ICD10 Depression

The 10/66 protocol.

Prince M, Ferri CP, Acosta D, et al. The protocols for the 10/66 Dementia Research Group population-based research programme. BMC Public Health 2007,7:165.

238 dementia cases238 dementia cases

355 controls355 controls

SNP studies (60 SNP studies (60 markers of markers of admixture)admixture)

APOE 4 in 2500 APOE 4 in 2500 population samplespopulation samples

Admixture and dementia

Box plot of African admixture distribution by ethno-racial identity (weighted)

white mixed black

race - blood test

0.000

0.200

0.400

0.600

0.800

Afr

‘White’ “Mixed” Black’

Ethno racial group

Dementia Dementia

N(%) 273N(%) 273No No

dementiadementia

N(%) 2247N(%) 2247

Adjusted1Adjusted1

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

APOE APOE Genotype Genotype

e2/e3e2/e3 24 (8.8%)24 (8.8%) 255 (11.4%)255 (11.4%) 0.96 (0.6-0.96 (0.6-1.4)1.4)

1.42 (0.3-1.42 (0.3-5.4)5.4)

1.00 (ref.)1.00 (ref.)

e2/e4e2/e4 2 (0.7%)2 (0.7%) 15 (0.7%)15 (0.7%)

e3/e3e3/e3 162 162 (59.3%)(59.3%)

1663 1663 (74.0%)(74.0%)

e3/e4e3/e4 77 77 (28.2%)(28.2%)

285 (12.7%)285 (12.7%) 2.59 (2.0-2.59 (2.0-3.3)3.3)

e4/e4e4/e4 8 (2.9%)8 (2.9%) 29 (1.3%)29 (1.3%) 2.88 (1.6-2.88 (1.6-5.3)5.3)

APOE Genotype by dementia status

  

Cuba – association of APOE genotype with dementia

DementiDementiaa

N 273 (%)N 273 (%)

No No dementidementiaa

N 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 alelles

00 186 (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

  

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 alleleallele

No 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

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<0.001

E3E3 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)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 alleleallele

N= 445N= 445

One APOE One APOE alleleallele

N=119N=119

Two APOE Two APOE alleleallele

N=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

Correlates of African admixture

socio-culturally constructed?

• Lower education

• Lower socioeconomic status

• More hazardous drinking

genetically mediated?

• Larger skulls and longer legs

• Lower triglyceride

• Higher ‘bad’ cholesterol (LDL, VLDL)

• Lower ‘good’ cholesterol (HDL)

• Higher e4 prevalence (but this does not mediate effect on lipids)

• Higher systolic blood pressure

• Increased risk of stroke - adjusted OR = 4.59 (1.09-19.3)

Conclusions

• No support for the hypotheses that genes linked to admixture may reduce the risk for dementia among Africans, or modify the effect of APOE genotype

• We will be able to look at effect modification with more power with our other admixed samples

• No evidence for population stratification in the estimation of the association between APOE and dementia

• Important effect of African ancestry on risk for stroke

• Potential to use admixture linkage analysis to identify genes linked to admixture responsible for this effect

• Alzheimer’s Disease International

• The 10/66 Dementia Research Group

• Our funders– The Wellcome Trust

• Institute of Psychiatry London , UK BMC Medical Genetics 2011

My thanks to