Plasma Alzheimer's disease biomarker variability: Amyloid-independent and amyloid-dependent factors

INTRODUCTION: We aimed to investigate which factors affect plasma biomarker levels via amyloid beta (Aβ)-independent or Aβ-dependent effects and improve the predictive performance of these biomarkers for Aβ positivity on positron emission tomography (PET). METHODS: A total of 2935 participants underwent blood sampling for measurements of plasma Aβ42/40 ratio, phosphorylated tau 217 (p-tau217; ALZpath), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) levels using single-molecule array and Aβ PET. Laboratory findings were collected using a routine blood test battery. RESULTS: Aβ-independent factors included hemoglobin and estimated glomerular filtration rate (eGFR) for p-tau217 and hemoglobin, eGFR, and triiodothyronine (T₃) for GFAP and NfL. Aβ-dependent factors included apolipoprotein E genotypes, body mass index status for Aβ42/40, p-tau217, GFAP, and NfL. However, these factors exhibited negligible or modest effects on Aβ positivity on PET. DISCUSSION: Our findings highlight the importance of accurately interpreting plasma biomarkers for predicting Aβ uptake in real-world settings. Highlights: We investigated factor–Alzheimer's disease plasma biomarker associations in a large Korean cohort. Hemoglobin and estimated glomerular filtration rate affect the biomarkers independently of brain amyloid beta (Aβ). Apolipoprotein E genotypes and body mass index status affect the biomarkers dependent on brain Aβ. Addition of Aβ-independent factors shows negligible effect in predicting Aβ positivity. Adjusting for Aβ-dependent factors shows a modest effect in predicting Aβ positivity.