Towards the future of ADRD diagnosis: combination of a brief digital cognitive battery and plasma biomarkers for diagnosis and prognosis of disease

Abstract

AbstractBackgroundScalable and accurate diagnostic markers of Alzheimer’s disease and related dementias (ADRD) are urgently needed. A combination of a sensitive brief digital cognitive assessment and plasma biomarkers could represent a promising scalable alternative to standard diagnostic procedures. We evaluated the performance of the TabCAT Brain Health Assessment Cognitive Score (BHA‐CS) and plasma Aβ42/40, pTau‐181, NfL, and GFAP at predicting concurrent Aβ positivity on CSF or PET, concurrent disease severity, and future functional decline.MethodParticipants were 309 subjectively or objectively impaired older adults enrolled in longitudinal observational studies at UCSF (Table 1), who completed a blood draw and TabCAT‐BHA at baseline. Biomarker concentrations were measured using commercially available Quanterix kits. Receiver operating characteristic analyses were used to determine the accuracy of combined BHA‐CS and plasma biomarkers in discriminating between Aβ+/‐ status on CSF/PET at baseline. Multiple regressions were used to examine baseline associations of BHA‐CS and plasma markers with disease severity measured by Clinical Dementia Rating Sum of Boxes (CDR‐SB). Linear mixed effect models were used to examine the associations of baseline BHA‐CS and biomarker values with longitudinal decline on CDR‐SB. All analyses controlled for age, sex, education, and baseline diagnosis.ResultpTau‐181 was the strongest predictor of Aβ positivity (AUC = .745; 95%CI: .656‐.833), with no significant improvements in the AUC with the addition of any combination of markers (Figure 1). In a combined model with all markers included simultaneously, BHA‐CS (B = ‐0.678, P<.001) and plasma NfL (B = 0.625, P = .01) were the only unique significant predictors of concurrent CDR‐SB. In a combined mixed model with all markers included simultaneously, baseline BHA‐CS, pTau‐181, NfL, and GFAP were unique significant predictors of CDR‐SB decline (Figure 2), and together accounted for 27% of longitudinal variance in CDR‐SB.ConclusionOur findings indicate unique and complementary roles of scalable digital cognitive and plasma biomarkers as diagnostic and prognostic markers of ADRD. At baseline, whereas pTau‐181 was most accurate at predicting Aβ positivity, a combination of BHA‐CS and NfL was most accurate at predicting concurrent disease severity. In longitudinal analyses, a model that combined baseline cognitive testing results and plasma pTau‐181, NfL, and GFAP was most accurate at predicting future decline.