Mixed effects models for cognitive trajectories by <i>APOE</i> ε4/G-score risk group.

<p>Abbreviations: TICS-m: Telephone interview for Cognitive Status-modified; high G-score: high genetic risk score; low G-score: low genetic risk score. Model included age, age², sex, sex*age, education, education*age, and group*age. Corresponding model results for the four-level variable and interaction terms are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0130419#pone.0130419.t002" target="_blank">Table 2</a>.</p

<i>APOE</i> ε4 and <i>TOMM40</i> ‘523-L with AD dementia in African Americans.

<p><i>APOE</i> ε4 and <i>TOMM40</i> ‘523-L with AD dementia in African Americans.</p

<i>APOE</i> ε4 and <i>TOMM40</i> ‘523-L with AD dementia in Caucasian Americans.

<p><i>APOE</i> ε4 and <i>TOMM40</i> ‘523-L with AD dementia in Caucasian Americans.</p

Cumulative hazards of incident AD dementia by <i>APOE</i> ε4 and <i>TOMM40</i> ‘523-L genotypes in African Americans.

<p>The figure illustrates cumulative hazards of incident AD dementia for representative female African Americans with mean age and education. For panel A, the blue solid curve represents cumulative hazard for non-ε4 carriers, the black dash curve for ε4 heterozygotes, and the red solid curve for ε4 homozygotes. For panel B, the blue solid curve represents cumulative hazards for non-‘523-L carriers, the black solid curve for ‘523-L heterozygotes, and the red dash curve for ‘523-L homozygotes.</p

<i>APOE</i> ε4-<i>TOMM40</i> ‘523 haplotypes and the risk of Alzheimer’s disease in older Caucasian and African Americans

<div><p>Patterns of linkage between the ε4 allele of Apolipoprotein E (<i>APOE</i>) and ‘523 poly-T alleles in the adjacent gene, <i>TOMM40</i>, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer’s disease (AD) is unclear. We compared the <i>APOE</i> ε4-<i>TOMM40</i> ‘523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia. Data came from three community based cohort studies of diverse participants. <i>APOE</i> genotypes were determined by polymorphisms of rs429358 and rs7412. <i>TOMM40</i> ‘523 genotypes were defined by the poly-T repeat length of rs10524523 (short [‘523-S]: poly-T ≤ 19, long [‘523-L]: 20 ≤ poly-T ≤ 29, and very long [‘523-VL]: poly-T ≥ 30). Cox proportional hazards models examined the effect of haplotype variation on the risk of incident AD dementia. A total of 1,848 Caucasian and 540 African American individuals were included in the study. In Caucasians, nearly none (0.8%) of the non-ε4 carriers and almost all (94.2%) of the ε4 carriers had ‘523-L. The classification was highly concordant. Each ε4 allele doubled the risk for AD dementia and the dose effect was evident. Almost identical effect size and effect pattern were observed for <i>TOMM40</i> ‘523-L. In African Americans, nearly none (1.1%) of the non-ε4 carriers had ‘523-L, but only 47.8% of the ε4 carriers had ‘523-L. The concordance was weaker compared with Caucasians. The effect patterns on incident AD dementia differed distinctively between ε4 and ‘523-L carriers. Further, both genotypic and allelic data support that among African Americans the ε4-‘523-L haplotype had stronger effect on risk of AD dementia than other ε4-‘523 haplotypes.</p></div

Cumulative hazards of incident AD dementia by <i>APOE</i> ε4 and <i>TOMM40</i> ‘523-L genotypes in Caucasian Americans.

<p>The figure illustrates cumulative hazards of incident AD dementia for representative female Caucasians with mean age and education. The blue solid curve represents cumulative hazard for non-ε4 carriers, the black solid curve for ε4 heterozygotes, and the red solid curve for ε4 homozygotes. Superimposed are the blue dash curve representing cumulative hazards for non-‘523-L carriers, the black dash curve for ‘523-L heterozygotes, and the red dash curve for ‘523-L homozygotes.</p

Strand specific haplotypes for ε3/4 heterozygotes in African Americans.

<p>Strand specific haplotypes for ε3/4 heterozygotes in African Americans.</p

‘523’ Allele frequencies in non US geographical cohorts (Far Eastern and West Africa).

<p>Genotypes determination was performed by Polymorphic, Inc. using a sequencing based assay.</p

<i>APOE</i> allele frequencies by ‘523’ genotypes in non US geographical cohorts (Far Eastern and West Africa).

<p>Genotypes determination was performed by Polymorphic, Inc.</p

<i>APOE</i> allele frequencies by ‘523’ genotypes in different ethnicities in the US.

<p><i>APOE</i> allele frequencies by ‘523’ genotypes in different ethnicities in the US.</p