Alzheimer's Imaging Consortium.

Area of Science:

• Neuroscience
• Biomarkers
• Neuroimaging

Background:

• Alzheimer's disease (AD) heterogeneity and non-AD factors complicate therapeutic development.
• Previous work identified discordance between tau (T) and neurodegeneration (N) using multi-modality imaging.
• This study simplified the approach using plasma p-tau217 and medial temporal lobe (MTL) morphometry.

Purpose of the Study:

• To investigate tau-neurodegeneration (T-N) mismatch patterns in the MTL using plasma p-tau217 and MRI.
• To identify distinct patient groups based on T-N discordance.
• To explore the clinical and cognitive implications of these T-N mismatch groups.

Main Methods:

• Included 349 ADNI participants with T1-MRI and plasma p-tau217.
• Segmented MTL into subregions and parcellated into super-points.
• Calculated T-N residuals and used weighted clustering to identify groups.

Main Results:

• Strong association found between p-tau217 and MTL atrophy.
• Three T-N mismatch groups identified: canonical (N∼T), vulnerable (N>T), and resilient (N
• The vulnerable group showed greater anterior MTL and limbic atrophy, worse cognitive ratings, and faster decline; the resilient group showed the opposite.

Conclusions:

• T-N mismatch in MTL using MRI and plasma biomarkers identified patient groups with varying vulnerability/resilience.
• The vulnerable group's patterns suggest underlying LATE-NC (Limbic-predominant Age-Related TDP-43 Encephalopathy Neuropathological Changes).
• This method offers a less invasive, cost-effective approach for stratifying individuals for therapeutic interventions.