ECRG4 as a novel diagnostic plasma marker detected in the early phase of Alzheimer's disease

Current therapeutic methods for Alzheimer's disease (AD) aim to delay its progression; therefore, developing a reliable method for diagnosing the early phases of the disease (EAD) is crucial. Based on the finding that the secretory protein Esophageal Cancer-Related Gene 4 (ECRG4) is elevated in the hippocampus of AD patients, we developed a new ECRG4 ELISA system. Here, we show that ECRG4 peptides, particularly those containing amino acids 108 to 132, are increased in the plasma of approximately 25% of mild cognitive impairment and half of AD patients, compared to non-dementia individuals. RNA sequencing analysis of the plasma revealed decreased levels of CHST3 mRNA, which is highly expressed in oligodendrocyte-lineage cells, in ECRG4-positive patients. We demonstrate that amino acids 71 to 107 exert cytotoxicity to oligodendrocytes in culture and decrease the intensity of the oligodendrocyte marker in the corpus callosum when injected into the brain. This results in extravascular IgG leakage due to the accumulation of oligodendrocyte precursor cells (OPCs), which regenerate myelin, around the blood vessels. Given that similar phenomena were detected in the brains of EAD patients, these results suggest that ECRG4 is involved in the progression of AD through vascular destruction in a manner dependent on oligodendrocyte defects. Overall design: EDTA-treated plasma (plasma) and cerebrospinal fluid (CSF) samples were obtained from patients diagnosed with dementia, including AD and normal pressure hydrocephalus, as well as those with MCI and non-dementia neurological disorders, such as multiple system atrophy and myopathy, using standard methods.