Biomarkers

Area of Science:

• Neuroscience
• Biomarkers in neurodegenerative diseases
• Clinical staging of Alzheimer's disease

Background:

• Revised Alzheimer's disease (AD) staging incorporates biological-clinical mismatch, categorizing individuals as vulnerable or resilient based on clinical impairment relative to biological stage.
• This study utilized plasma p-tau217 and 18F-flortaucipir PET (T2) biomarkers to assess mismatch against global clinical severity (CDR-SB).
• Investigated differences in brain structure, alpha-synuclein positivity, and longitudinal changes in cognition, tau accumulation, and atrophy among canonical, vulnerable, and resilient groups.

Purpose of the Study:

• To identify biological-clinical mismatch in Alzheimer's disease using tau biomarkers (p-tau217 and Tau-MaX) and clinical severity (CDR-SB).
• To investigate neurodegenerative differences, alpha-synuclein co-pathology, and longitudinal trajectories in canonical, vulnerable, and resilient groups.
• To validate the tau-cognitive mismatch model in an independent dataset.

Main Methods:

• Included amyloid-positive ADNI participants with available Tau PET or p-tau217 and CDR-SB scores.
• Defined mismatch using linear regression between tau burden (Tau-MaX or p-tau217) and CDR-SB, categorizing participants into canonical, vulnerable, and resilient groups.
• Analyzed medial temporal lobe (MTL) structure, brain-wide thickness, alpha-synuclein status, and longitudinal tau PET, atrophy, and cognitive trajectories, controlling for covariates. Replicated findings in the Penn ADRC dataset.

Main Results:

• Both Tau-MaX and p-tau217 showed moderate association with CDR-SB.
• Vulnerable individuals exhibited greater neurodegeneration in anterior MTL and temporolimbic regions and higher alpha-synuclein prevalence.
• The vulnerable group demonstrated accelerated cognitive decline independent of tau accumulation rate and faster atrophy in MTL and temporolimbic regions. Findings were consistent across ADNI and Penn ADRC datasets.

Conclusions:

• Tau-cognitive mismatch effectively identifies vulnerable individuals with distinct neurodegeneration patterns and alpha-synuclein co-pathology, overlapping with Limbic-predominant Age-Related TDP-43 Encephalopathy (LATE).
• Plasma-based tau biomarkers successfully identified similar vulnerable individuals in an independent cohort, suggesting clinical utility.
• This approach refines understanding of AD progression heterogeneity and identifies individuals requiring targeted interventions.