Biomarkers.

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Background:

• Amyloid and tau pathologies are key in Alzheimer's Disease (AD), with tau uniquely driving white matter (WM) microstructural damage via prion-like spread.
• Tau accumulation and WM decline precede clinical symptoms, underscoring their critical role in AD manifestation.
• Autosomal dominant AD (ADAD) offers a model for studying preclinical AD due to its uniform phenotype, early pathology, and precise disease staging.

Purpose of the Study:

• To investigate the preclinical relationship between tau accumulation and white matter microstructural integrity in ADAD.
• To characterize white matter integrity in ADAD mutation-carriers and non-carriers using advanced neuroimaging techniques.
• To determine the timing of white matter abnormalities relative to disease onset in ADAD.

Main Methods:

• Utilized data from the Dominantly Inherited Alzheimer Network (DIAN).
• Assessed white matter integrity using fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity via tract-based spatial statistics.
• Performed probabilistic tractography to extract white matter indices from the cingulum bundle and uncinate fasciculus, regions associated with tau accumulation hubs.

Main Results:

• Symptomatic ADAD mutation-carriers showed significantly altered whole-brain white matter microstructure compared to asymptomatic carriers and non-carriers.
• White matter abnormalities in mutation-carriers emerged concurrently with symptomatic progression.
• Tract-specific analyses revealed white matter microstructure differences in all mutation-carriers compared to non-carriers, emerging five years prior to the expected symptom onset in the cingulum bundle and uncinate fasciculus.

Conclusions:

• Global white matter differences are apparent near symptom onset in ADAD, but tracts near tau accumulation sites exhibit much earlier microstructural abnormalities.
• This suggests that ADAD white matter decline is not uniform and spatially correlates with tau accumulation, with damage occurring downstream of tau spread.
• Characterizing tau and white matter progression is crucial for understanding how tau drives cognitive symptom onset in ADAD.