Introduction: Blood-based biomarkers for Alzheimer's disease (AD) have the potential to improve diagnostic accessibility, but their clinical interpretation requires understanding of variability and biological influences.

Methods: We repeatedly sampled blood from 57 adults referred for lumbar puncture as part of a cognitive evaluation at a memory clinic. We measured serum phosphorylated- tau-181 (s-p-tau181) and plasma amyloid beta (Aβ)42/40 ratio (p-Aβ42/Aβ40) and evaluated the impact of renal and blood–brain barrier (BBB) function.

Results: Test–retest analysis revealed large variability of s-p-tau181 and small for p-Aβ42/Aβ40. Markers of renal function and BBB integrity significantly influenced s-p-tau181 levels, whereas p-Aβ42/Aβ40 was not affected.

Discussion: This study emphasizes the need for caution when interpreting longitudinal changes in s-p-tau181. Inter-individual variability is to a large degree due to susceptibility to biological influences where a novel association with integrity of BBB function were identified. These results have implications for the clinical application of blood-based biomarkers in AD diagnostics and monitoring.

Highlights: Blood phosphorylated- tau-181 (p-tau181) shows high test–retest variability in memory clinic patients. Blood amyloid beta (Aβ)42/Aβ40 ratio is stable but has poor diagnostic accuracy. Renal function and blood–brain barrier (BBB) integrity affect blood p-tau181 levels. Caution is needed when interpreting longitudinal changes in blood p-tau181. Renal and BBB disorders should be considered when assessing blood p-tau181.