Monitoring the Dynamics of Alzheimer's Disease Biomarkers and the APOE–Tau Axis via Human Cerebral Organoids with Immuno‐SERS

Abstract Noninvasive monitoring of Alzheimer's disease (AD) biomarkers is essential for early diagnosis and treatment efficacy. However, noninvasive monitoring of tau protein secretion, a key biomarker of AD, across developmental stages, age‐related variations, and the interaction between apolipoprotein E (APOE) and the tau protein axis is not yet accomplished. Here, the label‐free and non‐invasive detection of multiple tau variants dynamics across developmental stages, age‐related variants, and various APOE isogenic genotyes is presented to investigate the APOE–tau axis using human cerebral organoids (hCOs) combined with surface‐enhanced Raman spectroscopy (SERS). Principal component analysis (PCA) of SERS signals successfully identifies four developmental stages of hCOs: embryonic body, neuronal differentiation, maturation, and maintenance phases. Temporal dynamics of age‐related tau protein secretion are observed, reflecting characteristics associated with AD, which are diminished by astrocyte expression. PCA‐based dimensionality reduction of SERS signals further reveals distinct clustering for different APOE isogenic genotypes, with tau protein secretion increasing from APOE2/E2 to APOE4/E4, providing direct insight into the APOE–tau axis in AD. This study introduces a novel method for the non‐invasive clinical assessments of disease conditions, dynamics, and the relationship between APOE and tau in AD.