Use of local genetic ancestry to assess TOMM40 -523' and risk for Alzheimer disease.

ObjectiveHere, we re-examine TOMM40-523 as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) in Apolipoprotein E (APOE) epsilon 4 haplotypes.MethodsThe TOMM40-523 size was determined by fragment analysis and whole genome sequencing in homozygous APOE epsilon 3 and APOE epsilon 4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size.ResultsThe TOMM40-523 ' length did not modify risk for LOAD in APOE epsilon 4 haplotypes with EUR or AF LGA. Increasing length of TOMM40-523 ' was associated with a significantly reduced risk for LOAD in EUR APOE epsilon 3 haplotypes.ConclusionsAdjustment for LGA confirms that TOMM40-523 ' cannot explain the strong differential risk for LOAD between APOE epsilon 4 with EUR and AF LGA. Our study does confirm previous reports that increasing allele length of the TOMM40-523 ' repeat is associated with decreased risk for LOAD in carriers of homozygous APOE epsilon 3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGA APOE epsilon 3 allele haplotype.