White matter fractional anisotropy decreases precede hyperintensities in Alzheimer's disease

Area of Science:

• Neuroscience
• Neuropathology
• Radiology

Background:

• Alzheimer's disease (AD) involves beta-amyloid (Aβ) and tau pathology, but their impact on white matter (WM) degeneration is unclear.
• White matter integrity is crucial for cognitive function, and its degeneration is a hallmark of AD.
• Understanding the interplay between Aβ, tau, and WM changes is vital for AD diagnosis and treatment.

Purpose of the Study:

• To investigate the relationship between Aβ and tau deposition and both microstructural (fractional anisotropy, FA) and macrostructural (white matter hyperintensities, WMHs) white matter changes in AD.
• To examine longitudinal changes in WM markers across different stages of Aβ and tau pathology.
• To explore the influence of vascular risk factors on these associations.

Main Methods:

• Utilized positron emission tomography (PET) imaging to quantify Aβ and tau deposition in participants with varying AD pathology.
• Assessed microstructural WM integrity using fractional anisotropy (FA) from diffusion tensor imaging.
• Quantified macrostructural WM changes through white matter hyperintensities (WMHs) on MRI scans.
• Analyzed baseline and longitudinal data, considering vascular risk factors, in independent cohorts.

Main Results:

• Lower FA levels and faster FA decline rates were observed across the AD continuum, especially in tau-positive individuals.
• Tau deposition was significantly correlated with increased WMH burden and faster WMH progression, but not vice versa.
• These findings were consistent across two independent study cohorts, reinforcing their robustness.

Conclusions:

• Tau pathology is a primary driver of microstructural white matter degeneration in Alzheimer's disease, preceding macrostructural WM alterations.
• The study highlights tau's critical role in WM integrity, suggesting potential therapeutic targets for early intervention in AD.
• Findings emphasize the importance of monitoring WM degeneration and targeting tau clearance to maintain brain health in AD patients.