Physiological Confounders of Blood‐Based Alzheimer’s Disease Biomarkers in Middle‐Aged Asymptomatic Individuals

Abstract

AbstractBackgroundBlood‐based biomarkers represent a promising tool for Alzheimer’s disease (AD) clinical diagnosis and patient management. However, the identification of physiological factors that may influence their concentration levels in plasma is fundamental to warrant their clinical use, but more data is needed on whether such possible confounders result in clinically relevant changes. Here, we aim to identify physiological confounders of blood‐based AD biomarkers in a middle‐aged asymptomatic population.MethodThe Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal study following >4000 asymptomatic middle‐aged individuals. This study included 537 PESA participants, 370 of them with follow‐up data 4.7±0.6 years later. The concentrations of Aβ40, Aβ42, p‐tau181, GFAP and NFL in plasma were quantified using the Simoa pTau‐181 V2 and Neurology 4‐Plex E Advantage Kits. Potential confounders were also measured and included body mass index (BMI), as a proxy of blood volume; creatinine, as of kidney function; and aspartate (AST) and alanine aminotransferase (ALT), as of liver function. Stepwise regression was used to determine which confounders (predictors) are associated with plasma biomarkers (outcomes), adjusting for age, sex and APOE, both cross‐sectionally and in annual change rates (p<0.05). Participants were classified into normal and abnormal, based on standard cut‐off values for all potential confounders. Between‐group differences in plasma biomarkers were sought, and the abnormal group’s fold‐change was calculated.ResultThe studied sample had a mean age of 50.4±4.3 years, 441 were males and 88 APOE‐ε4 carriers (Figure 1). All blood‐based biomarkers but Aβ42/40 were negatively correlated with BMI and positively correlated with creatinine (Figure 2). ALT and AST were associated with Aβ40, Aβ42 and p‐tau181 but with opposite effects. Increases in BMI were associated with a decline in NFL and GFAP, while an increase in AST with a decline in amyloid and tau accumulation in plasma. Abnormally high BMI was associated with lower biomarker plasma concentrations, except for in Aβ42/40, with a maximum fold‐change of ‐12% for GFAP (Figure 3).ConclusionBMI, kidney and liver function are associated with plasma brain biomarkers levels in asymptomatic middle‐aged individuals. However, the magnitude of their effect is minor, with limited impact for their clinical applicability in individual patients.