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

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).

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.

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.

Our findings highlight the importance of accurately interpreting plasma biomarkers for predicting Aβ uptake in real-world settings.

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.