White matter tract integrity metrics reflect the vulnerability of late-myelinating tracts in Alzheimer's disease

• We investigated the vulnerability of late-myelinating tracts in AD using WMTI metrics.
• WMTI metrics are derived from the biophysical modeling of the DKI signal.
• These metrics indicate pathological features like axonal density and myelin integrity.
• WMTI metrics were largely stable in early-myelinating tracts through the course of AD.
• Axonal density loss & myelin breakdown were observed in late-myelinating tracts.

Post-mortem and imaging studies have observed that white matter (WM) degenerates in a pattern inverse to myelin development, suggesting preferential regional vulnerabilities influencing cognitive decline in AD. This study applied novel WM tract integrity (WMTI) metrics derived from diffusional kurtosis imaging (DKI) to examine WM tissue properties in AD within this framework. Using data from amnestic mild cognitive impairment (aMCI, n = 12), AD (n = 14), and normal control (NC; n = 15) subjects, mixed models revealed interaction effects: specific WMTI metrics of axonal density and myelin integrity (i.e. axonal water fraction, radial extra-axonal diffusivity) in late-myelinating tracts (i.e. superior and inferior longitudinal fasciculi) changed in the course of disease, but were stable in the initial stages for early-myelinating tracts (i.e. posterior limb of the internal capsule, cerebral peduncles). WMTI metrics in late-myelinating tracts correlated with semantic verbal fluency, a cognitive function known to decline in AD. These findings corroborate the preferential vulnerability of late-myelinating tracts, and illustrate an application of WMTI metrics to characterizing the regional course of WM changes in AD.