Staging Alzheimer's Disease Risk by Sequencing Brain Function and Structure, Cerebrospinal Fluid, and Cognition Biomarkers

J Alzheimers Dis. 2016 Oct 4;54(3):983-993. doi: 10.3233/JAD-160537.


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.

Keywords: Alzheimer’s disease; CARE index; biomarkers sequence; functional connectivity; stage.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / cerebrospinal fluid*
  • Alzheimer Disease / diagnostic imaging*
  • Alzheimer Disease / psychology
  • Biomarkers / cerebrospinal fluid
  • Brain / diagnostic imaging*
  • Brain / physiology*
  • Cognition / physiology
  • Cognitive Dysfunction / cerebrospinal fluid*
  • Cognitive Dysfunction / diagnostic imaging*
  • Cognitive Dysfunction / psychology
  • Databases, Factual
  • Female
  • Humans
  • Male
  • Middle Aged
  • Risk Factors


  • Biomarkers