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Introduction: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer's disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aß)42/Aß40 could predict continuous values for amyloid PET. Methods: CSF Aß42 and Aß40 were measured with automated immunoassays. Plasma Aß42 and Aß40 were measured with an immunoprecipitation-mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aß42/Aß40 with amyloid PET burden were modeled. Results: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was 69.0 ± 8.8 years. CSF Aß42/Aß40 predicted amyloid PET burden until a relatively high level of amyloid accumulation (69.8 Centiloids), whereas plasma Aß42/Aß40 predicted amyloid PET burden until a lower level (33.4 Centiloids). Discussion: CSF Aß42/Aß40 predicts the continuous level of amyloid plaque burden over a wider range than plasma Aß42/Aß40 and may be useful in AD staging. Highlights: Cerebrospinal fluid (CSF) amyloid beta (Aß)42/Aß40 predicts continuous amyloid positron emission tomography (PET) values up to a relatively high burden.Plasma Aß42/Aß40 is a comparatively dichotomous measure of brain amyloidosis.Models can predict regional amyloid PET burden based on CSF Aß42/Aß40.CSF Aß42/Aß40 may be useful in staging AD.
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BACKGROUND AND OBJECTIVES: To evaluate whether plasma biomarkers of amyloid (Aß42/Aß40), 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 CSF collection, and amyloid PET was performed in 103 participants (68%). Plasma Aß42/Aß40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aß42/Aß40 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 participants to have brain amyloidosis by CSF Aß42/Aß40 (22% vs 43% positive; p = 0.003). The receiver operating characteristic area under the curve of CSF Aß42/Aß40 status with the plasma biomarkers was as follows: Aß42/Aß40, 0.86 (95% 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 Aß42/Aß40 status with plasma Aß42/Aß40 that included covariates (age, sex, APOE ε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aß42/Aß40 positivity. In similar models based on plasma p-tau181, p-tau231, or NfL, AA participants had a lower probability of CSF Aß42/Aß40 positivity (odds ratio 0.31 [95% CI 0.13-0.73], 0.30 [0.13-0.71], and 0.27 [0.12-0.64], respectively). Models of amyloid PET status yielded similar findings. DISCUSSION: Models predicting brain amyloidosis using a high-performance plasma Aß42/Aß40 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 individuals.
