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

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. ### Competing Interest Statement The authors have declared no competing interest.