The etiology of blood‐based biomarkers for Alzheimer’s Disease in a population‐based sample of mid to late‐age males

Abstract

AbstractBackgroundThe amyloid‐tau‐neurodegeneration (ATN) framework has led to an increased focus on Alzheimer’s disease (AD) biomarkers. The costs and invasiveness of methods relying on cerebrospinal fluid or positron emission tomography imaging have led to 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.MethodWe therefore analyzed plasma beta amyloid (Ab40, Ab42, Ab42/40), total Tau (t‐tau), and neurofilament light (NFL) biomarkers based on a sample of 1,050 men aged 60 to 73 years (m=67.1, SD=2.57) from the Vietnam Era Twin Study of Aging (VETSA). Unlike AB and tau, NFL does not define AD; however, as a biomarker of neurodegeneration it serves as the N component in the ATN framework.ResultUnivariate analyses revealed that familial aggregation in Ab42, Ab42/40, t‐tau and NFL could be entirely explained by additive genetic influences accounting for 50% to 56% of the total variance. All remaining variances were unshared or unique environmental influences. For Ab40, additive genetic (31%) and shared environmental (44%) influences both contributed to total variance. In multivariate analyses, genetic influences accounted for 73% to 75% of the variance in the Ab biomarkers and 55% to 57% of the variance in t‐tau and NFL. The same analyses also revealed that Ab40 and Ab42 were statistically genetically identical and moderately correlated in terms of their environmental influences. All other bivariate associations ranged from small to moderate.ConclusionOur findings suggest that plasma biomarkers are heritable and that Ab40 and Ab42 share the same genetic influences. In contrast, genetic influences on plasma t‐tau and NFL are mostly unique and uncorrelated with plasma Ab in early old‐age men.