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

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.