Identifying Changepoints in Biomarkers During the Preclinical Phase of AD

Objective Several models have been proposed for the evolution of Alzheimer’s disease (AD) biomarkers. The aim of this study was to identify changepoints in a range of biomarkers during the preclinical phase of AD. Methods We examined nine measures based on cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and cognitive testing, obtained from 306 cognitively normal individuals, a subset of whom subsequently progressed to the symptomatic phase of AD. A changepoint model was used to determine which of the measures had a significant change in slope in relation to clinical symptom onset. Results All nine measures had significant changepoints, all of which preceded symptom onset, however the timing of these changepoints varied considerably. A single measure, CSF-tau, had an early changepoint (40 years prior to symptom onset). A group of measures, including the remaining CSF measures (CSF-Abeta and phosphorylated tau) and all cognitive tests had changepoints 10-15 years prior to symptom onset. A second group is formed by medial temporal lobe shape composite measures, with a five-year time difference between the right and left side (respectively nine and three years prior to symptom onset). Conclusions These findings highlight the long period of time prior to symptom onset during which AD pathology is accumulating in the brain. There are several significant findings, including the early changes in cognition and the laterality of the MRI findings. Additional work is needed to clarify their significance. ### Author Contributions Dr. Younes conducted the analyses and drafted the manuscript Dr. Moghekar played a major role in acquiring the data Dr. Albert interpreted the data and revised the manuscript Dr. Soldan revised the manuscript for intellectual content Dr. Pettigrew revised the manuscript for intellectual content Dr. Miller interpreted the data and revised the manuscript ### Disclosures Dr. Younes reports no disclosures Dr. Moghekar reports no disclosures Dr. Albert is a consultant to Eli Lilly Dr. Soldan reports no disclosures Dr. Pettigrew reports no disclosures Dr. Miller reports he has significant ownership in Anatomy Works, LLC, a relationship which is being handled by the University.