Plasma pTau181 is associated with impaired cognition in the Old Order Amish and adds additional information beyond the known genetic risk factors for AD

Abstract

AbstractBackgroundAs plasma biomarker assays have become more widely available, they are increasingly being used to characterize AD and related dementias. The Old Order Amish are a cultural and genetic isolate in the US that have participated in genetic studies for decades. This study investigated plasma phosphorylated tau at threonine‐181 (pTau181) in an Old Order Amish cohort to determine if the association with cognitive status is reproducible in this population.MethodOld Order Amish individuals over age 65 (n=467, mean age = 81.3, 60.6% female) in Indiana and Ohio were examined using a modified Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery. Each individual was assigned Impaired (n=155, mean age = 82.5, 56.8% female) or Unimpaired (n=312, mean age = 80.8, 62.5% female) cognitive status via consensus review of these examination results. The level of plasma pTau181 was measured using the pTau181 Advantage V2 assay from Quanterix. Genetic Risk Scores (GRS) were calculated using genome‐wide significant variants from Kunkle et al. (2019), weighted by log odds ratio estimates. A t‐test was used to compare plasma pTau181 levels between the Impaired and Unimpaired groups. Logistic regression was then used to model the contribution of age, sex, GRS, and plasma pTau181 on cognitive status.ResultWe found that the average level of plasma pTau181 was significantly higher in the Impaired group (2.46 pg/mL) compared to the Unimpaired group (2.01 pg/mL) at p<0.0001. A multivariable model found increasing age (OR=1.10, p=0.0002), male sex (OR=1.60, p=0.04), increasing GRS (OR=1.97, p<0.0001), and increasing plasma pTau181 (OR=1.46, p=0.001) associated with impaired cognitive status. The effect of GRS is mostly attributable to APOE.ConclusionThe result of these analyses indicates that pTau181 is associated with impaired cognitive status in the Old Order Amish, adding additional information beyond the known genetic risk factors for AD.