Does Preclinical Alzheimer Disease Affect White Matter Diffusion Restriction?

Researchers sought to identify and characterize amyloid-related white matter changes in preclinical Alzheimer disease using diffusional kurtosis imaging and biophysical modeling.

A link was established between the continuum in preclinical Alzheimer disease (AD) and diffusion restriction in white matter, likely to occur in areas that myelinate later in life and show early AD-related changes, in an analysis published in the Annals of Neurology

Potential mechanisms associated with diffusion restriction include innate immune activation/inflammation, myelin repair, and gliosis, thus implying nonamyloid pathologic changes on which to focus treatment development and disease monitoring at the earliest stages of the disorder.

For the study, the researchers sought to identify the microstructural changes in white matter that are associated with amyloid deposition at the preclinical stage of AD. They explored whether beta-amyloid–negative (AB–) and beta-amyloid–positive (AB+) participants differed in diffusional kurtosis imaging (DKI) — based conventional and modeling metrics, as well as whether these metrics were related to other biomarkers.

An ongoing, institutional review board–approved, prospective, 2-year, observational cohort study was conducted among community-dwelling cognitively unimpaired older adults between ages 45 and 85 years.

Eligibility criteria for the current study included the following: (1) no self-reported, previously diagnosed, or suspected cognitive impairment; (2) English as a first/primary language; (3) no contraindications to magnetic resonance imaging or positron emission tomography; and (4) no history of severe/unstable condition that affects cognition, including stroke, seizures, brain cancer, serious mental illness, or current substance or alcohol abuse. A total of 153 participants were enrolled in the present cohort study. 

The findings revealed significantly greater diffusion restriction (ie, higher fractional anisotropy [FA]/axonal water fraction [AWF] and lower mean diffusivity [MD]/extra-axonal radial diffusivity [De,]) in white matter in AB+ participants than in AB– participants (partial n2 = 0.08 to 0.19) — more notably in the extra-axonal space within primarily late myelinating tracts.

Diffusion metrics were predictive of amyloid status incrementally over age (area under the curve = 0.84), with modest, yet selective, associations. AWF, which is a known marker of axonal density, was associated with speed/executive functions and neurodegeneration. In contrast, De,— a known marker of gliosis and myelin repair — was associated with amyloid deposition and white matter hyperintensity volume.

The major limitations of the present study include the use of a convenience sample of mostly female, White, and well-educated participants, along with the lack of other biomarkers of AD with which the participants could be fully characterized within the research framework.

“Future work will endeavor to address these limitations to improve study generalizability and maximize relevance to ongoing AD biomarker research,” the researchers concluded.

Disclosure: None of the study authors has declared affiliations with biotech, pharmaceutical, and/or device companies.  


Benitez A, Jensen JH, Thorn K, et al. Greater diffusion restriction in white matter in preclinical Alzheimer disease. Ann Neurol. Published online March 13, 2022. doi:10.1002/ana.26353.