A Multi-Axis Framework for Late-Life Alzheimer's Disease Interpretation.

Area of Science:

• Neurology
• Biomarker Discovery
• Geriatric Medicine

Background:

• Late-life Alzheimer's disease (AD) diagnosis increasingly relies on biomarkers.
• However, amyloid positivity in adults aged ≥65 years often shows a discordant relationship with near-term cognitive decline.
• Amyloid PET scans detect fibrillar plaque burden but may not fully capture dynamic, neurotoxic amyloid processes like soluble assemblies.

Purpose of the Study:

• To re-evaluate the late-life AD spectrum by integrating multiple clinical and biomarker perspectives.
• To propose a pragmatic multi-axis framework for contextualizing discordant biomarker and clinical findings in older adults.
• To highlight testable predictions and prioritize longitudinal studies for refining risk stratification beyond plaque-centered models.

Main Methods:

• Review integrating four lenses: amyloid PET, plasma amyloid-β oligomerization tendency (MDS-OAβ), postoperative delirium (POD), and drug-linked biomarker trajectories.
• MDS-OAβ is presented as an activity-oriented readout potentially decoupling from plaque burden.
• POD serves as a stress-test phenotype indicating vulnerability and resilience.

Main Results:

• Identified discordances include PET positivity without decline, PET negativity with elevated MDS-OAβ, and delirium-associated decompensation.
• Contrasted rapid plaque removal by anti-amyloid antibodies with potential effects of Ginkgo biloba on oligomer biology.
• Proposed a framework encompassing plaque burden, amyloid activity, downstream engagement, and vulnerability/resilience.

Conclusions:

• A multi-axis framework is needed to contextualize complex late-life AD biomarker profiles.
• Activity-oriented biomarkers and stress phenotypes may refine risk stratification beyond current plaque-centric approaches.
• Longitudinal, multi-marker studies are crucial for validating this integrated approach in older adults.