Associations of the APOE e2 and e4 alleles and polygenic profiles comprising APOE-TOMM40-APOC1 variants with Alzheimer's disease biomarkers

Capturing the genetic architecture of Alzheimer's disease (AD) is challenging because of the complex interplay of genetic and non-genetic factors in its etiology. It has been suggested that AD biomarkers may improve the characterization of AD pathology and its genetic architecture. Most studies have focused on connections of individual genetic variants with AD biomarkers, whereas the role of combinations of genetic variants is substantially underexplored. We examined the associations of the APOE epsilon 2 and epsilon 4 alleles and polygenic profiles comprising the epsilon 4-encoding rs429358, TOMM40 rs2075650, and APOC1 rs12721046 polymorphisms with cerebrospinal fluid (CSF) and plasma amyloid beta (A beta 40 and A beta 42) and tau biomarkers. Our findings support associations of the epsilon 4 alleles with both plasma and CSF A beta 42 and CSF tau, and the epsilon 2 alleles with baseline, but not longitudinal, CSF A beta 42 measurements. We found that the epsilon 4-bearing polygenic profiles conferring higher and lower AD risks are differentially associated with tau but not A beta 42. Modulation of the effect of the epsilon 4 alleles by TOMM40 and APOC1 variants indicates the potential genetic mechanism of differential roles of A beta and tau in AD pathogenesis.