Effect of Race on Prediction of Brain Amyloidosis by Plasma Aβ42/Aβ40, Phosphorylated Tau, and Neurofilament Light

Abstract

Objective:To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231) and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups.Methods:Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, APOE ε4 carrier status and cognitive status. Each participant underwent blood and cerebrospinal fluid (CSF) collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively.Results:There were 76 matched pairs of AA and NHW participants (n=152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were APOE ε4 carriers and 91% were cognitively normal. AA were less likely than NHW to have brain amyloidosis by CSF Aβ42/Aβ40 (22% versus 43% positive, p = 0.003). The Receiver Operating Characteristic Area Under the Curve (ROC AUC) of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% confidence intervals [CI] 0.79-0.92); p-tau181, 0.76 (0.68-0.84); p-tau231, 0.69 (0.60-0.78); and NfL, 0.64 (0.55-0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex, APOE ε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-tau181, p-tau231 or Nfl, AA had a lower probability of CSF Aβ42/Aβ40 positivity (Odds Ratio [OR] 0.31 [95% CI 0.13-0.73], OR 0.30 [0.13-0.71]) and OR 0.27 [0.12-0.64], respectively. Models of amyloid PET status yielded similar findings.Conclusions:Models predicting brain amyloidosis using a high performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA.

Associations of plasma phosphorylated tau181 and neurofilament light chain with brain amyloid burden and cognition in objectively defined subtle cognitive decline patients

“…The rapid development of ultrasensitive assays makes it possible to predict the levels of proteins associated with pathological AD in blood. Some plasma biomarkers have been shown to correlate closely with CSF biomarkers and imaging markers 3,4 . The core blood biomarkers of AD include Aβ42 (or Aβ42/40 ratio), phosphorylated tau181 (p‐tau181), neurofilament light chain (NfL), and total tau (T‐tau), which reflect Aβ pathology, tau pathology, and neuronal damage, respectively 5,6 …”

“…Some plasma biomarkers have been shown to correlate closely with CSF biomarkers and imaging markers. 3,4 The core blood biomarkers of AD include Aβ42 (or Aβ42/40 ratio), phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), and total tau (Ttau), which reflect Aβ pathology, tau pathology, and neuronal damage, respectively. 5,6 Various experimental results have shown that lower plasma Aβ42/Aβ40 ratio was associated with higher amyloid cortical burden, 7,8 faster Aβ accumulation rates, 9 greater cognitive declines, 10,11 and increased risk of developing AD dementia at follow-up.…”

Potential utility of plasma p-tau and NfL as surrogate biomarkers for preventive clinical trials

“…ADNI includes a selective population of highly educated, mostly white participants, generalizable to current clinical trials that have a similar population profile but do not represent a diverse general population. Thus, it would be highly desirable to reproduce our findings in a more diverse population-based cohort 45, 46 . Furthermore, the use of different blood assays for measuring the plasma biomarkers could lead to different results.…”

Comparison of plasma and CSF biomarkers in predicting cognitive decline

“…Importantly, analytes may have differential performance based on the disease stage of the cohort under investigation. In cohorts of cognitively normal individuals, single molecule array (Simoa) measures of p‐tau181 may be less accurate in the detection of PET amyloid status whereas mass spectrometry measures of Aβ42/Aβ40 perform relatively well 20,21 …”

“…In cohorts of cognitively normal individuals, single molecule array (Simoa) measures of p-tau181 may be less accurate in the detection of PET amyloid status whereas mass spectrometry measures of Ab42/Ab40 perform relatively well. 20,21 Although multiple studies have examined the relationship of cognitive decline with either plasma Ab42/Ab40 [22][23][24] or plasma NfL, 15,[25][26][27] it is unclear whether plasma measures of Ab42/Ab40 or NfL perform similarly to CSF measures of these analytes. Further, there are major differences in assay performance, especially for plasma Ab42/Ab40 assays, 28,29 and there have not been any wellpowered studies of cognitive decline as predicted by highperformance measurements of plasma Ab42/Ab40.…”