Presymptomatic Increase of an Extracellular RNA in Blood Plasma Associates with the Development of Alzheimer’s Disease

• Published in: Current biology Vol. 30; no. 10; pp. 1771 - 1782.e3
• Main Authors: Yan, Zhangming, Zhou, Zixu, Wu, Qiuyang, Chen, Zhen Bouman, Koo, Edward H., Zhong, Sheng
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 18.05.2020
• Subjects: Alzheimer’s disease; biomarker; brain; extracellular RNA; liquid biopsy; longitudinal data; PHGDH; plasma; presymptomatic diagnosis; SILVER-seq; SILVER-seq; Alzheimer’s disease; extracellular RNA; PHGDH; biomarker; plasma; brain; liquid biopsy; longitudinal data; presymptomatic diagnosis
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2020.02.084

The extracellular RNAs (exRNAs) from human biofluid have recently been systematically characterized. However, the correlations of biofluid exRNA levels and human diseases remain largely untested. Here, considering the unmet need for presymptomatic biomarkers of sporadic Alzheimer’s disease (AD), we leveraged the recently developed SILVER-seq (small-input liquid volume extracellular RNA sequencing) technology to generate exRNA profiles from a longitudinal collection of human plasma samples. These 164 plasma samples were collected from research subjects 70 years or older with up to 15 years of clinical follow-up prior to death and whose clinical diagnoses were confirmed by pathological analysis of their post mortem brains. The exRNAs of AD-activated genes and transposons in the brain exhibited a concordant trend of increase in AD plasma in comparison with age-matched control plasma. However, when we required statistical significance with multiple testing adjustments, phosphoglycerate dehydrogenase (PHGDH) was the only gene that exhibited consistent upregulation in AD brain transcriptomes from 3 independent cohorts and an increase in AD plasma as compared to controls. We validated PHGDH’s serum exRNA and brain protein expression increases in AD by using 5 additional published cohorts. Finally, we compared the time-course exRNA trajectories between “converters” and controls. Plasma PHGDH exRNA exhibited presymptomatic increases in each of the 11 converters during their transitions from normal to cognitive impairment but remained stable over the entire follow-up period in 8 out of the 9 control elderly subjects. These data suggest the potential utilities of plasma exRNA levels for screening and longitudinal exRNA changes as a presymptomatic indication of sporadic AD. •Blood plasma exRNAs from a 15-year clinical follow-up are sequenced by SILVER-seq•Brain expression levels of brain-specific genes correlate with presence of exRNA•PHGDH exhibits AD-associated mRNA and protein increase in brain and exRNA increase•Presymptomatic increase of plasma PHGDH exRNA predicts the clinical diagnosis of AD Yan et al. report a concordant increase of plasma extracellular RNA with brain mRNA and protein levels of the PHGDH gene in Alzheimer’s subjects. A presymptomatic increase of PHGDH extracellular RNA in human blood plasma is predictive of the development of Alzheimer’s disease.