Spatial organization of protein aggregates on red blood cells as physical biomarkers of Alzheimer’s disease pathology

Quantifying physical differences of protein aggregates implicated in Alzheimer’s disease (AD), in blood, could provide crucial information on disease stages. Here, red blood cells (RBCs) from 50 patients with neurocognitive complaints and 16 healthy individuals were profiled using an atomic force microscope (AFM). AFM measurements revealed patient age– and stage of neurocognitive disorder–dependent differences in size, shape, morphology, assembly, and prevalence of protein aggregates on RBCs, referred to as physical biomarkers. Crystals composed of fibrils were exclusively detected on RBCs for AD patients aged above 80 years. Fibril prevalence was negatively correlated with the cerebrospinal fluid (CSF) β-amyloid (Aβ) 42/40 ratio and was observed to be higher in the Aβ-positive patient category. Using a cutoff of ≥40% fibril prevalence, the CSF Aβ status was classified with 88% accuracy (sensitivity 100%, specificity 73%). The merits and challenges in integrating physical biomarkers in AD diagnosis are discussed.