Alzheimer's Imaging Consortium

Area of Science:

• Neuroscience
• Genetics
• Biomedical Research

Background:

• Amyloid and tau pathologies are key in Alzheimer's Disease (AD).
• Tau pathology, spreading like a prion, distinctly damages white matter microstructure through axonal injury.
• In autosomal dominant AD (ADAD), tau accumulation and white matter decline precede clinical symptoms, offering a model to study early AD pathogenesis.

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 versus non-carriers using advanced neuroimaging techniques.
• To determine the timing of white matter abnormalities relative to disease stage and symptom 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.

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 disease progression.
• Tract-specific analyses revealed white matter microstructure differences in all mutation-carriers versus non-carriers, emerging five years before symptom onset in the cingulum bundle and uncinate fasciculus.

Conclusions:

• While global white matter changes are near symptom onset, specific tracts near tau accumulation sites show abnormalities much earlier in ADAD.
• White matter decline in ADAD is not uniform and spatially correlates with tau accumulation, suggesting tau drives white matter damage.
• Early, tract-specific white matter decline precedes cognitive symptoms, underscoring its role in ADAD pathogenesis and providing targets for therapeutic intervention.