Combining plasma p‐tau231 and glial fibrillary acidic protein produces higher discriminative accuracy for amyloid positivity than other blood‐based biomarker combinations

Abstract

AbstractBackgroundPlasma phosphorylated tau (p‐tau)231 is an emerging blood‐based biomarker that has shown great promise for early identification of individuals at risk of Alzheimer’s disease (AD). However, it is unclear if this biomarker is sufficient as a standalone test or if diagnostic classification improves when simultaneously considering other plasma biomarkers. We investigated various plasma biomarkers, individually and in combination, in relation to cerebrospinal fluid (CSF) amyloid positivity.MethodVanderbilt Memory and Aging Project participants free of clinical dementia and stroke (n = 155, 72±6 years, 33% female) underwent fasting lumbar puncture and blood draw. CSF β‐amyloid42 (Aβ42) and β‐amyloid40 (Ab40) and plasma p‐tau231, glial fibrillary acidic protein (GFAP), Aβ42, Aβ40, and neurofilament light chain (NfL) were analyzed in batch. The Aβ42/40 ratio was used for all analyses and CSF amyloid positivity was defined as Aβ42/40 ratio <0.072. Logistic regression models related each biomarker to amyloid positivity, adjusting for age, sex, race/ethnicity, apolipoprotein E‐ε4 status, and cognitive status. Subsequent models included p‐tau231 as the predictor in a base model with other biomarkers being added individually and then in combination with other biomarkers to the base model. Models were compared using likelihood ratio test (LRTest) and Akaike Information Criterion (AIC) values.ResultIn single predictor models, p‐tau231 (C‐index = 0.87, p = 0.005) and GFAP (C‐index = 0.87, p = 0.01) were associated with amyloid positivity, while other biomarkers were not (p‐values>0.35). In models including p‐tau231 and various biomarker combinations, p‐tau231 remained significant in each model (p‐values<0.02). In comparison to the base model with p‐tau231 only, models adding GFAP (AIC = 143.8, LRTest p = 0.008), GFAP and NfL (AIC = 145.5, LRTest p = 0.02), and GFAP and Aβ42/40 (AIC = 145.8, LRTest p = 0.03) improved prediction of amyloid positivity. The model including plasma p‐tau231 and GFAP was the best fitting model (C‐index = 0.89).ConclusionIn this sample of community‐dwelling older adults free of clinical dementia, we found plasma p‐tau231 and GFAP were associated with amyloid positivity. Models including both p‐tau231 and GFAP performed best, and adding additional plasma biomarkers to this combination did not produce a better fitting model. Taken together, these findings highlight the utility of plasma p‐tau231 for screening for amyloid status and suggest that including plasma GFAP will improve discriminative accuracy.