Alzheimer's Imaging Consortium.

Area of Science:

• Neuroscience
• Neurology
• Biomedical Imaging

Background:

• Alzheimer's disease (AD) exhibits heterogeneous tau pathology distribution, including hemispheric asymmetry.
• The underlying mechanisms of tau asymmetry remain unclear, prompting investigation into connectivity and amyloid-beta (Aβ) influences.

Purpose of the Study:

• To investigate whether tau asymmetry in Alzheimer's disease is associated with inter-hemispheric connectivity or Aβ distribution.
• To determine if reduced connectivity restricts tau spread or if Aβ asymmetry indicates hemisphere-specific vulnerability.

Main Methods:

• Analysis of 837 Aβ-positive participants from the Swedish BioFINDER-2 cohort using tau-PET scans.
• Comparison of inter-hemispheric structural and functional connectivity across tau asymmetry groups (left asymmetric, symmetric, right asymmetric).
• Investigation of the association between Aβ and tau laterality, validated in independent cohorts, and longitudinal assessment of Aβ laterality's impact on tau progression.

Main Results:

• No significant differences in inter-hemispheric functional or structural connectivity were found between tau asymmetry groups.
• A strong association was observed between tau and Aβ laterality patterns, replicated across multiple cohorts.
• Baseline Aβ asymmetry predicted longitudinal tau laterality progression, particularly in individuals without baseline tau pathology.

Conclusions:

• Tau asymmetry in Alzheimer's disease is not driven by macro-scale inter-hemispheric connectivity differences.
• Findings suggest that hemispheric vulnerability to Aβ pathology is the primary driver of tau asymmetry.
• This highlights the role of Aβ distribution in shaping tau pathology patterns in AD.