Associations Between Amyloid and Tau Pathology, and Connectome Alterations, in Alzheimer's Disease and Mild Cognitive Impairment

J Alzheimers Dis. 2021;82(2):541-560. doi: 10.3233/JAD-201457.

Abstract

Background: The roles of amyloid-β and tau in the degenerative process of Alzheimer's disease (AD) remain uncertain. [18F]AV-45 and [18F]AV-1451 PET quantify amyloid-β and tau pathology, respectively, while diffusion tractography enables detection of their microstructural consequences.

Objective: Examine the impact of amyloid-β and tau pathology on the structural connectome and cognition, in mild cognitive impairment (MCI) and AD.

Methods: Combined [18F]AV-45 and [18F]AV-1451 PET, diffusion tractography, and cognitive assessment in 28 controls, 32 MCI, and 26 AD patients.

Results: Hippocampal connectivity was reduced to the thalami, right lateral orbitofrontal, and right amygdala in MCI; alongside the insula, posterior cingulate, right entorhinal, and numerous cortical regions in AD (all p < 0.05). Hippocampal strength inversely correlated with [18F]AV-1451 SUVr in MCI (r = -0.55, p = 0.049) and AD (r = -0.57, p = 0.046), while reductions in hippocampal connectivity to ipsilateral brain regions correlated with increased [18F]AV-45 SUVr in those same regions in MCI (r = -0.33, p = 0.003) and AD (r = -0.31, p = 0.006). Cognitive scores correlated with connectivity of the right temporal pole in MCI (r = -0.60, p = 0.035) and left hippocampus in AD (r = 0.69, p = 0.024). Clinical Dementia Rating Scale scores correlated with [18F]AV-1451 SUVr in multiple areas reflecting Braak stages I-IV, including the right (r = 0.65, p = 0.004) entorhinal cortex in MCI; and Braak stages III-VI, including the right (r = 0.062, p = 0.009) parahippocampal gyrus in AD.

Conclusion: Reductions in hippocampal connectivity predominate in the AD connectome, correlating with hippocampal tau in MCI and AD, and with amyloid-β in the target regions of those connections. Cognitive scores correlate with microstructural changes and reflect the accumulation of tau pathology.

Keywords: 18F-AV-1451; 18F-AV-45; Alzheimer’s disease; amyloid; connectome; diffusion tensor imaging; magnetic resonance imaging; mild cognitive impairment; positron emission tomography; tau protein.

Publication types

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

MeSH terms

  • Aged
  • Alzheimer Disease* / diagnosis
  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / psychology
  • Amyloid beta-Peptides / metabolism*
  • Carbolines / pharmacology
  • Cognition / physiology
  • Cognitive Dysfunction* / diagnosis
  • Cognitive Dysfunction* / metabolism
  • Cognitive Dysfunction* / physiopathology
  • Connectome / methods*
  • Contrast Media / pharmacology
  • Correlation of Data
  • Diffusion Tensor Imaging / methods
  • Female
  • Hippocampus / diagnostic imaging
  • Hippocampus / pathology
  • Humans
  • Male
  • Mental Status and Dementia Tests
  • Positron-Emission Tomography
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Carbolines
  • Contrast Media
  • tau Proteins
  • 7-(6-fluoropyridin-3-yl)-5H-pyrido(4,3-b)indole