Table 2 Contexts of use for inflammatory markers in AD

Diagnosis and Disease Confirmation

• Might address incongruence between AT(N) biomarkers and clinical outcomes.

• AT(N) biomarkers provide biofluid correlates of accumulating neuropathology from none to severe.

• These biomarkers can be staged with relative independence from each other.

• Relative specificity/usefulness of a single biomarker is dependent on the disease-associated effect size (after accounting for inter-individual variability).

• Clearly defined, gold-standard neuroinflammatory outcomes for biomarker development are lacking

• To date, inflammatory markers have restricted pathologic correlates, limiting opportunities for validation.

• Non-degenerative causes can temporarily or chronically alter inflammatory marker levels or profiles, which impact single time point utility in diagnosis.

Risk stratification/ Endophenotyping

• Might provide better risk stratification of people with similar AT(N) profiles.

• Might identify subgroups useful for clinical trial design.

• AT(N) biomarkers have limited role in risk stratification beyond distinction from people with similar cognitive status and AT(N) biomarkers.

• There is no consensus on the temporal sequencing of neuroinflammation relative to AT(N). Inflammation is tightly regulated, which makes disequilibrium between markers more difficult to detect than level changes. Surrogate markers of neuroinflammatory processes need to be empirically defined.

• Examination of disease-associated inflammatory profiles in the context of inflammaging is needed for risk stratification (similar to MRI measures of atrophy).

Prognosis

• Might identify rapid vs. slow decliners.

• Use of AT(N) biomarkers for prognosis is based on distinction from those free of neuropathology.

• Inflammation is tightly regulated which makes disequilibrium between markers more difficult to detect than level changes. Surrogate markers of neuroinflammatory processes need to be empirically defined.

• Markers useful for predicting cognitive and/or functional decline are likely to vary according to disease stage.

Disease monitoring

• Might be useful in monitoring rates of disease progression and response to emerging therapeutics.

• AT(N) biomarkers are useful for measuring target engagement.

• They may also be useful as surrogate markers of downstream treatment effects.

• However, small longitudinal changes in AT(N) biomarkers limit their role in natural history studies.

• Longitudinal disease-associated changes need to be distinguished from effects of aging/inflammaging.

• This may be useful for assessment of predicted inflammatory activation (e.g., monoclonal antibodies).

Safety

• Useful for assessing and predicting possible adverse effects linked to therapies (for patients) or exposure to environmental agents (in the general population).

• These markers may be important for the identification of individuals for whom specific therapies should not be administered.

• None currently.

• Empirical and potentially distinct biomarkers will be needed for Adverse Events and Serious Adverse Events.