Diffusion MRI relates to plasma Aβ42/40 in PET negative participants without dementia

Alzheimers Dement. 2024 Apr;20(4):2830-2842. doi: 10.1002/alz.13693. Epub 2024 Mar 5.


Introduction: Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid-β (Aβ42/40) positivity in Aβ positron emission tomography (PET) negative individuals.

Methods: Diffusion free-water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aβ plasma-/PET- (NC = 22, MCI = 60), plasma+/PET- (NC = 5, MCI = 20), and plasma+/PET+ (AD dementia = 21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross-sectionally and the relationships between imaging, plasma and PET biomarkers were assessed.

Results: Plasma+/PET- demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma-/PET-. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET-. Composite brain FW correlated with plasma Aβ42/40 and p-tau181.

Discussion: FW imaging changes distinguish plasma Aβ42/40 positive and negative groups, independent of group differences in cognitive status, Aβ PET status, and other plasma biomarkers (i.e., t-tau, p-tau181, glial fibrillary acidic protein, neurofilament light).

Highlights: Plasma Aβ42/40 positivity is associated with brain microstructure decline. Plasma+/PET- demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET- demonstrated decreased FAt in 66 total GM and WM regions. Whole-brain FW correlated with plasma Aβ42/40 and p-tau181 measures. Plasma+/PET- demonstrated decreased cortical volume and thickness.

Keywords: Alzheimer's disease; amyloid; biomarker; diffusion; free‐water; magnetic resonance imaging.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Biomarkers
  • Cognitive Dysfunction* / metabolism
  • Diffusion Magnetic Resonance Imaging
  • Humans
  • Positron-Emission Tomography / methods
  • tau Proteins


  • Amyloid beta-Peptides
  • Biomarkers
  • tau Proteins