Structural Connectivity Alterations Along the Alzheimer's Disease Continuum: Reproducibility Across Two Independent Samples and Correlation with Cerebrospinal Fluid Amyloid-β and Tau

J Alzheimers Dis. 2018;61(4):1575-1587. doi: 10.3233/JAD-170553.


Background: Gray matter changes associated with the progression of Alzheimer's disease (AD) have been thoroughly studied. However, alterations in white matter tracts have received less attention, particularly during early or preclinical stages of the disease.

Objective: To identify the structural connectivity changes across the AD continuum.

Methods: We performed probabilistic tractography in a total of 183 subjects on two independent samples that include control (n = 68) and preclinical AD individuals (n = 28), patients diagnosed with mild cognitive impairment (MCI) due to AD (n = 44), and AD patients (n = 43). We compared the connectivity between groups, and with CSF Aβ42 and tau biomarkers.

Results: We observed disconnections in preclinical individuals, mainly located in the temporal lobe. This pattern of disconnection spread to the parietal and frontal lobes at the MCI stage and involved almost all the brain in AD. These findings were not driven by gray matter atrophy.

Discussion: Using tractography, we were able to identify white matter changes between subsequent disease stages and, notably, also in preclinical AD. Therefore, this method may be useful for detecting early and specific brain structural changes during preclinical AD stage.

Keywords: Alzheimer’s disease; biomarkers; connectivity; diffusion MRI; magnetic resonance imaging; mild cognitive impairment; preclinical stage; tractography.

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

  • Aged
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / diagnosis*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / cerebrospinal fluid*
  • Atrophy / pathology
  • Biomarkers / cerebrospinal fluid
  • Case-Control Studies
  • Cognitive Dysfunction / diagnosis
  • Cohort Studies
  • Disease Progression
  • Female
  • Gray Matter / pathology*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Reproducibility of Results
  • Spain
  • White Matter / pathology*
  • tau Proteins / cerebrospinal fluid*


  • Amyloid beta-Peptides
  • Biomarkers
  • tau Proteins