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) ε4 haplotypes. METHODS: The TOMM40-523′ size was determined by fragment analysis and whole genome sequencing in homozygous APOE ε3 and APOE ε4 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 ε4 haplotypes with EUR or AF LGA. Increasing length of TOMM40-523′ was associated with a significantly reduced risk for LOAD in EUR APOE ε3 haplotypes. CONCLUSIONS: Adjustment for LGA confirms that TOMM40-523′ cannot explain the strong differential risk for LOAD between APOE ε4 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 ε3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGA APOE ε3 allele haplotype.