P4‐133: Aromatase variants modify risk for Alzheimer's disease in a multiethnic female cohort

Abstract

Genetic variants that affect estrogen activity may influence risk for Alzheimer's disease (AD). However, most studies have been conducted in Caucasian ethnic groups, and few polymorphisms have been assessed in a multi-ethnic cohort in which the members have all been evaluated in a consistent manner. Examination of polymorphisms in multiethnic groups which are evaluated without taking ancestry into account may have several limitations, including a loss of significant association due to different allele frequencies, different linkage disequilibrium patterns between ethnicities, or differences in the distribution of comorbid conditions and risk factors by ethnic group. We investigated the influence of CYP19 polymorphisms on risk for AD in a multiethnic cohort of women, with ethnicity assessed by genetic population ancestry markers (AIMs) as well as by self-identified ethnicity. W e hypothesized that genetic variants would affect risk for AD differently in groups with different population ancestries due to varying allele frequencies as well as disparate exposure environmental factors. 1686 women participating in the Washington Heights Inwood Columbia Aging Project (WHICAP), were followed at 18–24 month intervals. Data from standardized assessments, including neurological examination and a neuropsychological battery, were used to make an AD diagnosis. Using multivariate logistic regression, we examined risk for AD associated with 41 single-nucleotide polymorphisms (SNPs) on the CYP19 gene, controlling for age at time of evaluation, BMI, APOE status, current smoking, and current or past diabetes mellitus. Risk for AD was associated with six SNPs in women of predominantly Caucasian AIMs-defined ancestry (rs4775935, rs727479, rs17647719, s1902586, rs10163138, and rs7168331). Of these, rs4775935 and rs727479 were also associated with decreased risk of AD in women of admixed/ Hispanic AIMs ancestry. Two separate SNPs (rs6493495 and rs11070843) were found to be protective in women of predominantly African AIMs-based ancestry. Our findings suggest that CYP19 genetic variants play a role in risk for AD in women and that the risk alleles vary by population ancestry and self-identified ethnicity, possibly due to different linkage disequilibrium patterns or differences in the prevalence of comorbid risk factors for AD.