Statistical Model of Dynamic Markers of the Alzheimer's Pathological Cascade

J Gerontol B Psychol Sci Soc Sci. 2018 Aug 14;73(6):964-973. doi: 10.1093/geronb/gbx156.


Objectives: Alzheimer's disease (AD) is a progressive disease reflected in markers across assessment modalities, including neuroimaging, cognitive testing, and evaluation of adaptive function. Identifying a single continuum of decline across assessment modalities in a single sample is statistically challenging because of the multivariate nature of the data. To address this challenge, we implemented advanced statistical analyses designed specifically to model complex data across a single continuum.

Method: We analyzed data from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1,056), focusing on indicators from the assessments of magnetic resonance imaging (MRI) volume, fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic activity, cognitive performance, and adaptive function. Item response theory was used to identify the continuum of decline. Then, through a process of statistical scaling, indicators across all modalities were linked to that continuum and analyzed.

Results: Findings revealed that measures of MRI volume, FDG-PET metabolic activity, and adaptive function added measurement precision beyond that provided by cognitive measures, particularly in the relatively mild range of disease severity. More specifically, MRI volume, and FDG-PET metabolic activity become compromised in the very mild range of severity, followed by cognitive performance and finally adaptive function.

Conclusion: Our statistically derived models of the AD pathological cascade are consistent with existing theoretical models.

Publication types

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

MeSH terms

  • Activities of Daily Living / psychology
  • Aged
  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / pathology*
  • Biomarkers
  • Brain / diagnostic imaging
  • Brain / pathology
  • Case-Control Studies
  • Disease Progression
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Models, Statistical
  • Neuroimaging
  • Neuropsychological Tests
  • Positron-Emission Tomography


  • Biomarkers