Abstract The amyloid-tau-neurodegeneration (ATN) framework has led to an increased focus on Alzheimer’s disease (AD) biomarkers. The cost and invasiveness of obtaining biomarkers via cerebrospinal fluid has motivated efforts to develop sensitive blood-based biomarkers. Although AD is highly heritable, the biometric genetic and environmental etiology of blood-based biomarkers has never been explored. We therefore, analyzed plasma beta-amyloid (Aβ40, Aβ42, Aβ42/40), total tautau (t-tautau), and neurofilament light (NFL) biomarkers in a sample of 1,050 men aged 60 to 73 years (m=68.2, SD=2.5) from the Vietnam Era Twin Study of Aging (VETSA). Unlike Aβ and tautau, NFL does not define AD; however, as a biomarker of neurodegeneration it serves as the N component in the ATN framework. Univariate estimates suggest that familial aggregation in Aβ42, Aβ42/40, t-tau, and NFL is entirely explained by additive genetic influences accounting for 40%-58% of the total variance. All remaining variance is associated with unshared or unique environmental influences. For Aβ40, a additive genetic (31%), shared environmental (44%), and unshared environmental (25%) influences contribute to the total variance. In the more powerful multivariate analysis of Aβ42, Aβ40, t-tau, and NFL, heritability estimates range from 32% to 58%. Aβ40 and Aβ42 are statistically genetically identical (r g = 1.00, 95%CI = 0.92,1.00) and are also moderately environmentally correlated (r e = 0.66, 95%CI = 0.59, 0.73). All other genetic and environmental associations were non-significant or small. Our results suggest that plasma biomarkers are heritable and that Aβ40 and Aβ42 share the same genetic influences, whereas the genetic influences on plasma t-tau and NFL are mostly unique and uncorrelated with plasma Aβ in early old-age men.

The genetic and environmental etiology of blood-based biomarkers related to risk of Alzheimer’s Disease in a population-based sample of early old-age men