Abstract
The generation of new neurons persists into adulthood in the human hippocampus and can be modulated by the circulatory systemic environment. Hippocampal neurogenesis is important for learning and memory and is altered in Alzheimer’s Disease (AD). Evaluating the hippocampal neurogenic process during disease progression could therefore identify neurogenesis as an important target for AD prevention and intervention as well as a biomarker for early disease detection. In this study, we used a human hippocampal progenitor cell line to design an in vitro assay evaluating over time the neurogenic impact of the systemic milieu (i.e. serum) of individuals with mild cognitive impairment (MCI) as they either converted to AD or remained cognitively stable. Cells were exposed to serum collected over several years from the same patients. Cellular phenotyping and linear mixed effects models for repeated measures revealed that decreased proliferation, increased apoptotic hippocampal progenitor cell death and increased hippocampal neurogenesis characterized progression from MCI to AD. Using stepwise logistic regression and machine learning we show that these cellular readouts for the baseline serum sample and years of education of the patient are significant predictors of conversion from MCI to AD, already 3.5 years before AD clinical diagnosis. Finally, serum proteomic analyses indicated pathways linked to the cellular readouts distinguishing MCI to AD converters from non-converters. The proposed assay is thus not only promising for AD pre-clinical diagnosis, but it also provides a proxy into temporal changes of the hippocampal neurogenic process during disease progression.
One Sentence Summary In this study, we demonstrate for the first time that the systemic environment (i.e. blood serum) of mild cognitively impaired patients differentially alters human hippocampal progenitor cell fate to predict conversion to Alzheimer’s Disease up to 3.5 years before clinical diagnosis.
