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

Objective Here, 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) e4 haplotypes. Methods The TOMM40-523′ size was determined by fragment analysis and whole genome sequencing in homozygous APOE e3 and APOE e4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size. Results The TOMM40-523′ length did not modify risk for LOAD in APOE e4 haplotypes with EUR or AF LGA. Increasing length of TOMM40-523′ was associated with a significantly reduced risk for LOAD in EUR APOE e3 haplotypes. Conclusions Adjustment for LGA confirms that TOMM40-523′ cannot explain the strong differential risk for LOAD between APOE e4 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 e3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGA APOE e3 allele haplotype.