Biomarkers.

Area of Science:

• Neuroscience
• Biomarker Research
• Gerontology

Background:

• Alzheimer's disease (AD) is a complex neurodegenerative disorder causing progressive cognitive decline.
• Understanding AD's multiple timescales is vital for diagnostics and therapeutics.
• This study compares amyloid and tau PET clocks with novel multi-biomarker staging methods.

Purpose of the Study:

• To compare the performance of amyloid and tau PET clocks against novel staging methods.
• To evaluate staging methods that integrate multiple biomarkers and clinical measures.
• To assess staging accuracy across the full Alzheimer's disease continuum.

Main Methods:

• Utilized longitudinal data from 1064 Aβ-positive and 384 Aβ-negative participants.
• Derived amyloid and tau PET clocks and employed nonlinear mixed-effects modeling for alternative stagings.
• Assessed alignment quality using Spearman correlation with clinical, fluid, and imaging biomarkers; investigated age effects.

Main Results:

• Multi-biomarker (amyloid PET, tau PET, cognition) staging showed wider sensitivity and better biomarker alignment than PET clocks.
• Amyloid PET clocks performed well in preclinical/prodromal stages; tau PET clocks were less effective except in later stages.
• Age adjustment improved alignment quality for all staging methods.

Conclusions:

• Integrating multiple biomarkers and clinical data enhances Alzheimer's disease staging.
• Amyloid and tau PET clocks are valuable but have limitations in staging across the full AD continuum.
• Future PET clocks should use advanced statistical models with regularization and age adjustments to avoid overfitting.