Abstract Background Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid-β (Aβ) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2 . Methods HP genotypes were imputed in 29 cohorts from the Alzheimer’s Disease (AD) Genetics Consortium (N=22,651). Associations between the HP polymorphism and AD risk and age of onset through APOE interactions were investigated using regression models. Results The HP polymorphism significantly impacts AD risk and age at onset in European-descent individuals (and in meta-analysis with African Americans) by modifying both the protective effect of APOEε2 and the detrimental effect of APOEε4 , especially for APOEε4 carriers. Discussion The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.

A Haptoglobin (HP) Structural Variant Alters the Effect of APOE Alleles on Alzheimer’s Disease