Genetic architecture of Alzheimer’s disease-related plasma biomarkers

Alzheimer's disease-related plasma biomarker interrelationships and factors underlying these associations remain poorly understood. To address this, we studied the heritability of plasma biomarkers and their associations with cognition. This study included 696 twins, aged 65-85, without a diagnosis of Alzheimer's disease or related dementias. Plasma amyloid beta 42 and 40, phosphorylated tau (p-tau) 181 and 217, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified with Simoa HD-X, and cognition was assessed with cCOG. Heritability of plasma biomarkers was assessed with multivariate twin models and associations with cognition with linear mixed effect models. Phenotypic associations varied from 0.22 between p-tau181 and GFAP to 0.73 between p-tau181 and p-tau217, and the heritability estimates ranged from 0.39 (p-tau181) to 0.66 (GFAP). Genetic and environmental correlations were 0.32-0.67 and 0.06-0.78, with the strongest correlations observed between p-tau181 and p-tau217. P-tau181 and p-tau217 were associated with cognition (β = -0.12; 95% CI: -0.19--0.04 and β = -0.19; 95% CI: -0.26--0.12, respectively). The observed phenotypic and genetic associations highlight shared underlying mechanisms among plasma biomarkers. Despite p-tau181 and p-tau217 having the strongest genetic and environmental correlations, neither approached unity, implying unique genetic and environmental factors. Our results offer insight into the genetic architecture of diagnostic and progression markers of Alzheimer's disease and inform their use in future gene-finding studies.