“Does African ancestry protect against dementia? A population-based case-control study in 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, Cuba Centro Nacional de Genetica, Havana,Cuba Centre for Public Mental Health, KCL, UK

Population 11,6 millons Life expectancy Men 79 years Women 80 years Dementia´s prevalence % ( cases ) Incidence rate 21.7 per 1000/year ( new cases/year) Mortality rate in dementia people per 1000/year

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.

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 Cuba 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 BY SEX Male Female BY AGE * Incidence rate/ 1000 pyr Incidence of dementia by sex and age, Cuba Cohort 65 years and over N=2728

Risk factors for incident dementia Age group 1.79 ( ) Male gender 1.27 ( ) Education level 0.79 ( ) Leg length 1.02 ( ) Skull circ 1.06 ( ) Smoker 0.77 ( ) Hypertension 1.35 ( ) Parkinsonism score 1.18 ( ) Fish Frequency 0.40 ( ) Hazardous drinker 1.66 ( ) Stroke 2.84 ( ) APOE ( ) FH Dementia 1.39 ( )

Main source of admixture 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 diagnosis DSM IV Dementia DSM 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 cases 355 controls SNP studies (60 markers of admixture) APOE 4 in 2500 population samples Admixture and dementia

Box plot of African admixture distribution by ethno-racial identity (weighted) ‘White’ “Mixed” Black’ Ethno racial group

Dementia N(%) 273 No dementia N(%) 2247 Adjusted1 PR (95%CI) APOE Genotype e2/e3 24 (8.8%) 255 (11.4%) 0.96 ( ) 1.42 ( ) 1.00 (ref.) e2/e4 2 (0.7%) 15 (0.7%) e3/e3 162 (59.3%) 1663 (74.0%) e3/e4 77 (28.2%) 285 (12.7%) 2.59 ( ) e4/e4 8 (2.9%) 29 (1.3%) 2.88 ( ) APOE Genotype by dementia status

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 ( ) 2.6 ( ) Number of ApoE4 alelles (68.1) 1918 (85.4) 1.00 (ref.) 1 79 (28.9) 300 (13.4) 2.35 ( ) 2.6 ( ) 2 8 (2.9) 29 (1.3) 2.45 ( ) 2.9 ( ) * Adjusted age, sex and education

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 ( ) ( ) ( ) ( ) 6.34 Interaction term 0.56 ( ) * p<0.006

APOE allele frequency White n=1677 (72%)Mixedn=394(17%)Blackn=261(11%) P-value test for trend E <0.001 E E Association between any E4 and dementia 2.84( )2.38( ) Overall association between E4 and any dementia 2.58 ( ) Adjusted for race2.50( ) APOE allele frequency by ethno-racial identity

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( )0.19 ( ) 0.35( ) P = 0.01 European mean 95% CI 0.82( ) ( )0.62( ) P = Native american 0.03( )0.03( )0.03( ) P = 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 ( )

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