title: Staging Alzheimer's Disease Risk by Sequencing Brain Function and Structure, Cerebrospinal Fluid, and Cognition Biomarkers.
abstract: This study aims to develop a composite biomarker that can accurately measure the sequential biological stages of Alzheimer's disease (AD) on an individual level. We selected 144 subjects from the Alzheimer's Disease Neuroimaging Initiative 2 datasets. Ten biomarkers, from brain function and structure, cerebrospinal fluid, and cognitive performance, were integrated using the event-based probabilistic model to estimate their optimal temporal sequence (Soptimal). We identified the numerical order of the Soptimal as the characterizing Alzheimer's disease risk events (CARE) index to measure disease stage. The results show that, in the Soptimal, hippocampal and posterior cingulate cortex network biomarkers occur first, followed by aberrant cerebrospinal fluid amyloid-β and p-tau levels, then cognitive deficit, and finally regional gray matter loss and fusiform network abnormality. The CARE index significantly correlates with disease severity and exhibits high reliability. Our findings demonstrate that use of the CARE index would advance AD stage measurement across the whole AD continuum and facilitate personalized treatment of AD.
authors: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Guangyu
authors: G
authors: Chen
authors: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.|Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China.
authors: Hao
authors: H
authors: Shu
authors: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Gang
authors: G
authors: Chen
authors: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: B Douglas
authors: BD
authors: Ward
authors: Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Piero G
authors: PG
authors: Antuono
authors: Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute and Medical School of Southeast University, Nanjing, Jiangsu, China.
authors: Zhijun
authors: Z
authors: Zhang
authors: Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Shi-Jiang
authors: SJ
authors: Li
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging* / Q000523:psychology; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging* / Q000502:physiology*; D003071:Cognition / Q000502:physiology; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000000981:diagnostic imaging* / Q000523:psychology; D016208:Databases, Factual; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors
chemical_list: D015415:Biomarkers
keywords: Alzheimer’s disease; CARE index; biomarkers sequence; functional 
  connectivity; stage