Clinical Scorecard: Plasma Biomarker Patterns in Aging: Unraveling In Vivo Neurodegeneration

At a Glance

Key Highlights

• Three distinct plasma biomarker profiles identified correlating with neuropathological features: Profile 1 (low p-tau217, NFL, GFAP; high Aβ42/40), Profile 2 (elevated p-tau217, GFAP; high AD pathology), Profile 3 (elevated NFL, GFAP; vascular pathologies).
• Mixed neuropathologies are common in aging brains, with nearly 80% having at least two different neuropathological changes including AD, CAA, LATE, and Lewy bodies.
• Plasma biomarkers p-tau217 and GFAP are strongly associated with AD-related pathologies, while NFL is a non-specific marker of neuronal injury; biomarkers for TDP-43 and α-synuclein pathologies remain lacking.

Guideline-Based Recommendations

Diagnosis

• Use plasma biomarkers such as p-tau217, Aβ42/40, NFL, and GFAP to aid in vivo detection of neurodegenerative pathologies, especially Alzheimer's disease.
• Interpret plasma biomarker profiles in context of mixed pathologies common in aging brains.
• Recognize current limitations in plasma biomarkers for detecting TDP-43 (LATE) and α-synuclein (Lewy body) pathologies.

Management

• Incorporate plasma biomarker testing as scalable tools to support personalized medicine approaches in cognitive impairment.
• Consider biomarker profiles when evaluating patients with mild cognitive impairment or dementia to inform underlying pathology.

Monitoring & Follow-up

• Monitor plasma biomarker levels longitudinally to assess progression of neurodegenerative processes, noting that timing of sampling relative to disease stage affects interpretation.
• Recognize that plasma biomarker levels may change over years and may not fully reflect pathology if sampling is distant from clinical endpoints.

Risks

• Be aware of potential misclassification due to overlapping pathologies and biomarker profile heterogeneity.
• Understand that plasma biomarkers currently do not detect all relevant neuropathologies, limiting diagnostic completeness.

Patient & Prescribing Data

Older adults with cognitive impairment or at risk for neurodegenerative diseases in community settings

Plasma biomarker profiles can guide diagnosis and stratification but require integration with clinical and neuropathological data; no direct treatment implications yet established from biomarker patterns alone.

Clinical Best Practices

• Use a combination of plasma biomarkers rather than single markers to better characterize neurodegenerative pathology patterns.
• Interpret biomarker data alongside clinical phenotype and consider potential co-existing pathologies common in aging brains.
• Recognize the need for development and validation of plasma biomarkers for α-synuclein and TDP-43 pathologies to improve diagnostic accuracy.
• Account for the timing of plasma sampling relative to disease progression when evaluating biomarker levels.
• Apply data-driven approaches such as latent profile analysis to identify biomarker patterns in research and potentially clinical practice.

References

• Neuropathologic correlates of distinct plasma biomarker profiles in community-living older adults by Yu et al.
• FDA approval of plasma biomarkers for clinical use
• Plasma p-tau217 as a biomarker for amyloid and tau pathology
• Seeding amplification assays for α-synuclein detection in CSF