Advances in the ability to utilize plasma biomarkers to assess AD pathology provided new tools for assessing patients with cognitive impairment. With the emergence of anti-amyloid therapies, efficient diagnostic evaluation is needed to help identify treatment candidates accurately and timely. Combining biomarkers could provide a scalable diagnostic evaluation to identify AD patients for these therapies.

Determine whether combining plasma beta amyloid 42/40 and p-tau217 could achieve >90 sensitivity and specificity in evaluating patients at an ADRC for possible Alzheimer’s disease (AD).

Patients from the 1Florida ADRC with clinical evaluations and PET scan data (n=276; 39.1% prevalence) were evaluated for Abeta42/40 and apoprotein E4 (ApoE4) proteotype status by LC-MS/MS and p-tau217 by immunoassay. A likelihood score model was determined for each biomarker and the combination of Abeta42/40 and p-tau217 with or without ApoE4 status. Model performance included the use of two cut points for PET positivity.

For the intended use cohort (46.0% prevalence of PET-positivity), a combination of Aβ42/40, p-tau217, and APOE4 allele count provided the best model with a receiver operating characteristic area under the curve of 0.942 and with cut points fixed at 91% sensitivity and 91% specificity yielding 88% positive predictive value (PPV), 91% negative predictive value (NPV), and 87% accuracy for identifying amyloid PET status. Inclusion of APOE4 allele count also reduced the percentage of patients with indeterminate risk by 33% (from 15% to 10%). The model and cut points categorized the real-world clinical specimens as having 42% (1,822) high, 51% (2,204) low, and 7% (300) indeterminant likelihood for PET positivity.

Combining plasma biomarkers for Abeta42/40 and p-tau217 shows significant promise as a scalable approach when evaluating patients with cognitive impairment for potential AD pathology.  These data suggest that utilization of Abeta42/40 and p-tau217 tests together can accurately assess AD pathology with >90% sensitivity and specificity.