Acceptable performance of blood biomarker tests of amyloid pathology - recommendations from the Global CEO Initiative on Alzheimer's Disease.

Anti-amyloid treatments for early symptomatic Alzheimer disease have recently become clinically available in some countries, which has greatly increased the need for biomarker confirmation of amyloid pathology. Blood biomarker (BBM) tests for amyloid pathology are more acceptable, accessible and scalable than amyloid PET or cerebrospinal fluid (CSF) tests, but have highly variable levels of performance. The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to consider the minimum acceptable performance of BBM tests for clinical use. Amyloid PET status was identified as the reference standard. For use as a triaging test before subsequent confirmatory tests such as amyloid PET or CSF tests, the BBM Workgroup recommends that a BBM test has a sensitivity of ≥90% with a specificity of ≥85% in primary care and ≥75-85% in secondary care depending on the availability of follow-up testing. For use as a confirmatory test without follow-up tests, a BBM test should have performance equivalent to that of CSF tests - a sensitivity and specificity of ~90%. Importantly, the predictive values of all biomarker tests vary according to the pre-test probability of amyloid pathology and must be interpreted in the complete clinical context. Use of BBM tests that meet these performance standards could enable more people to receive an accurate and timely Alzheimer disease diagnosis and potentially benefit from new treatments.

A retrospective cohort of tumor-induced osteomalacia and case series of malignant disease.

OBJECTIVE: We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with tumor-induced osteomalacia (TIO), with a focus on patients with non-localizing and malignant TIO. METHODS: This is a retrospective cohort of TIO patients in an academic medical center, diagnosed between January 1998 to May 2023. We described their demographics, biochemistries, tumor features, localization, treatment and complications. RESULTS: Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. 20 (40%) had persistent disease due to wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus or baseline fibroblast growth factor-23 (FGF23) levels between localizing versus non-localizing groups, and malignant versus non-malignant groups. Lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. 60% of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R=0.566, p<0.001) but was not associated with malignancy risk (p=0.479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (p=0.025), and recurrence after initial cure (p=0.013) were factors significantly associated with malignancy. The non-localizing group had lower survival than localizing group (p=0.0097). CONCLUSIONS: TIO is a condition with significant morbidity. Very high FGF23 level and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in non-localizing TIO should be further explored.

Plasma biomarkers of Alzheimer's disease in the continuum of dementia with Lewy bodies.

INTRODUCTION: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease. METHODS: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans. RESULTS: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB. DISCUSSION: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP.

Performance of the Lumipulse plasma Aß42/40 and pTau181 immunoassays in the detection of amyloid pathology.

INTRODUCTION: This study evaluated the performance of the Lumipulse plasma beta-amyloid (Aß) 42/40 and pTau181 compared to other assays to detect an abnormal amyloid-positron emission tomography (PET). METHODS: Plasma samples from cognitively unimpaired (N = 179) and MCI/AD dementia (N = 36) individuals were retrospectively evaluated. Plasma Aß42/40 and pTau181 were measured using the Lumipulse and Simoa immunoassays. An immunoprecipitation mass spectrometry (IP-MS) assay for plasma Aß42/40 was also evaluated. Amyloid-PET status was the outcome measure. RESULTS: Lumipulse and IP-MS Aß42/40 exhibited the highest diagnostic accuracy for detecting an abnormal amyloid-PET (areas under the curve [AUCs] of 0.81 and 0.84, respectively). The Lumipulse and Simoa pTau181 assays exhibited lower performance (AUCs of 0.74 and 0.72, respectively). The Simoa Aß42/40 assay demonstrated the lowest diagnostic accuracy (AUC 0.57). Combining Aß42/40 and pTau181 did not significantly improve performance over Aß42/40 alone for Lumipulse (AUC 0.83) or over pTau181 alone for Simoa (AUC 0.71). DISCUSSION: The Lumipulse Aß42/40 assay showed similar performance to the IP-MS Aß42/40 assay for detection of an abnormal amyloid-PET; and both assays performed better than the two p-tau181 immunoassays. The Simoa Aß42/Aß40 assay was the least accurate at predicting an abnormal amyloid-PET status. Highlights: Lumipulse plasma Aß42/Aß40 AUC for abnormal amyloid-PET detection was 0.81.This performance was comparable to previously reported IP-MS and higher than Simoa.Performance of Alzheimer's disease blood biomarkers varies between assays.

Comparison of plasma biomarkers and amyloid PET for predicting memory decline in cognitively unimpaired individuals.

BACKGROUND: We compared the ability of several plasma biomarkers versus amyloid positron emission tomography (PET) to predict rates of memory decline among cognitively unimpaired individuals. METHODS: We studied 645 Mayo Clinic Study of Aging participants. Predictor variables were age, sex, education, apolipoprotein E (APOE) ε4 genotype, amyloid PET, and plasma amyloid beta (Aß)42/40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and p-tau217. The outcome was a change in a memory composite measure. RESULTS: All plasma biomarkers, except NfL, were associated with mean memory decline in models with individual biomarkers. However, amyloid PET and plasma p-tau217, along with age, were key variables independently associated with mean memory decline in models combining all predictors. Confidence intervals were narrow for estimates of population mean prediction, but person-level prediction intervals were wide. DISCUSSION: Plasma p-tau217 and amyloid PET provide useful information about predicting rates of future cognitive decline in cognitively unimpaired individuals at the population mean level, but not at the individual person level.

Modeling the temporal evolution of plasma p-tau in relation to amyloid beta and tau PET.

INTRODUCTION: The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co-evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers. METHODS: We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aß) PET, tau PET, plasma p-tau217, p-tau181, and glial fibrillary acidic protein (GFAP) as endpoints. RESULTS: Individual timing of plasma p-tau progression was strongly associated with Aß PET and GFAP progression. In the population, GFAP became abnormal first, then Aß PET, plasma p-tau, and tau PET temporal meta-regions of interest when applying cut points based on young, cognitively unimpaired participants. DISCUSSION: Plasma p-tau is a stronger indicator of a temporally linked response to elevated brain Aß than of tau pathology. While Aß deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p-tau and Aß PET was the strongest. HIGHLIGHTS: Plasma p-tau progression was more strongly associated with Aß than tau PET. Progression on plasma p-tau was associated with Aß PET and GFAP progression. P-tau181 and p-tau217 become abnormal after Aß PET and before tau PET. GFAP became abnormal first, before plasma p-tau and Aß PET.

Vascular risk, gait, behavioral, and plasma indicators of VCID.

INTRODUCTION: Cost-effective screening tools for vascular contributions to cognitive impairment and dementia (VCID) has significant implications. We evaluated non-imaging indicators of VCID using magnetic resonance imaging (MRI)-measured white matter (WM) damage and hypothesized that these indicators differ based on age. METHODS: In 745 participants from the Mayo Clinic Study of Aging (≥50 years of age) with serial WM assessments from diffusion MRI and fluid-attenuated inversion recovery (FLAIR)-MRI, we examined associations between baseline non-imaging indicators (demographics, vascular risk factors [VRFs], gait, behavioral, plasma glial fibrillary acidic protein [GFAP], and plasma neurofilament light chain [NfL]) and WM damage across three age tertiles. RESULTS: VRFs and gait were associated with diffusion changes even in low age strata. All measures (VRFs, gait, behavioral, plasma GFAP, plasma NfL) were associated with white matter hyperintensities (WMHs) but mainly in intermediate and high age strata. DISCUSSION: Non-imaging indicators of VCID were related to WM damage and may aid in screening participants and assessing outcomes for VCID. HIGHLIGHTS: Non-imaging indicators of VCID can aid in prediction of MRI-measured WM damage but their importance differed by age. Vascular risk and gait measures were associated with early VCID changes measured using diffusion MRI. Plasma markers explained variability in WMH across age strata. Most non-imaging measures explained variability in WMH and vascular WM scores in intermediate and older age groups. The framework developed here can be used to evaluate new non-imaging VCID indicators proposed in the future.

Lack of observed interference by therapeutic monoclonal antibodies in select commonly utilized immunoassays.

BACKGROUND: Therapeutic monoclonal antibodies (tmabs) have been hypothesized to interfere with immunoassay measurements, although studies investigating this potential new class of interference are lacking. This study evaluated the effects of tmabs used in cancers ipilimumab (Bristol Myers Squibb), nivolumab (Bristol Myers Squibb), pembrolizumab (Merck) and autoimmune disorders adalimumab (AbbVie), infliximab (Janssen) and vedolizumab (Takeda) in common immunoassays used in the clinical laboratory. METHODS: Residual sera from 10 randomly chosen patients were split into two tubes and spiked with same volume (approximately 5 % final volume) of either saline (control) or 6 tmabs (final concentration of 100 µg/mL each). Concentrations from sixteen analytes in 19 different assays were assessed: TSH (Roche and Beckman), free thyroxine (Roche and Siemens), cortisol (Beckman), Cancer Antigens (CA): CA19-9 (Beckman), CA15-3 (Roche), CA125 (Roche), and CA27.29 (Siemens), carcinoembryonic antigen (Beckman), alpha-fetoprotein (Beckman), thyroglobulin (Beckman) and thyroglobulin antibodies (Beckman), thyroid peroxidase antibody (Beckman), beta-human chorionic gonadotropin (Roche and Beckman), total prostate-specific antigen (Roche), parathyroid hormone (Roche) and antinuclear antibodies IgG (Werfen). The tmab spiked residual sera were compared with matched saline spiked sera and percent error was assessed against allowable total error defined from biological variation or CLIA limits. RESULTS: None of the tested immunoassays were affected by the presence of the tmabs, in samples within or outside assay reference intervals. The median % error among all immunoassays ranged between -2.0% (for TSH) to 2.7% (for TPO Ab assay). CONCLUSION: These findings demonstrate no detectable tmab interference for the assessed immunoassays using spiked preparations of the tmabs in residual human sera. The findings are limited to the tmabs and immunoassays studied here.

Thyroglobulin and thyroglobulin antibody: an updated clinical and laboratory expert consensus.

OBJECTIVE: Thyroglobulin measurement is the cornerstone of modern management of differentiated thyroid cancer, with clinical decisions on treatment and follow-up based on the results of such measurements. However, numerous factors need to be considered regarding measurement with and interpretation of thyroglobulin assay results. DESIGN: The present document provides an integrated update to the 2013 and 2014 separate clinical position papers of our group on these issues. METHODS: Issues concerning analytical and clinical aspects of highly-sensitive thyroglobulin measurement will be reviewed and discussed based on an extensive analysis of the available literature. RESULTS: Thyroglobulin measurement remains a highly complex process with many pitfalls and major sources of interference, especially anti-thyroglobulin antibodies, need to be assessed, considered and, when necessary, dealt with appropriately. CONCLUSIONS: Our expert consensus group formulated 53 practical, graded recommendations for guidance on highly-sensitive thyroglobulin and TgAb in laboratory and clinical practice, especially valuable where current guidelines do not offer sufficient guidance.

Association of Plasma Biomarkers of Alzheimer Disease With Cognition and Medical Comorbidities in a Biracial Cohort.

BACKGROUND AND OBJECTIVES: Recent advances in blood-based biomarkers offer the potential to revolutionize the diagnosis and management of Alzheimer disease (AD), but additional research in diverse populations is critical. We assessed the profiles of blood-based AD biomarkers and their relationships to cognition and common medical comorbidities in a biracial cohort. METHODS: Participants were evaluated through the Mayo Clinic Jacksonville Alzheimer Disease Research Center and matched on age, sex, and cognitive status. Plasma AD biomarkers (ß-amyloid peptide 1-42 [Aß42/40], plasma tau phosphorylated at position 181 [p-tau181], glial fibrillary acidic protein [GFAP], and neurofilament light) were measured using the Quanterix SiMoA HD-X analyzer. Cognition was assessed with the Mini-Mental State Examination. Wilcoxon rank sum tests were used to assess for differences in plasma biomarker levels by sex. Linear models tested for associations of self-reported race, chronic kidney disease (CKD), and vascular risk factors with plasma AD biomarker levels. Additional models assessed for interactions between race and plasma biomarkers in predicting cognition. RESULTS: The sample comprised African American (AA; N = 267) and non-Hispanic White (NHW; N = 268) participants, including 69% female participants and age range 43-100 (median 80.2) years. Education was higher in NHW participants (median 16 vs 12 years, p < 0.001) while APOE ε4 positivity was higher in AA participants (43% vs 34%; p = 0.04). We observed no differences in plasma AD biomarker levels between AA and NHW participants. These results were unchanged after stratifying by cognitive status (unimpaired vs impaired). Although the p-tau181-cognition association seemed stronger in NHW participants while the Aß42/40-cognition association seemed stronger in AA participants, these findings did not survive after excluding individuals with CKD. Female participants displayed higher GFAP (177.5 pg/mL vs 157.73 pg/mL; p = 0.002) and lower p-tau181 (2.62 pg/mL vs 3.28 pg/mL; p = 0.001) levels than male participants. Diabetes was inversely associated with GFAP levels (ß = -0.01; p < 0.001). DISCUSSION: In a biracial community-based sample of adults, we observed that sex differences, CKD, and vascular risk factors, but not self-reported race, contributed to variation in plasma AD biomarkers. Although some prior studies have reported primary effects of race/ethnicity, our results reinforce the need to account for broad-based medical and social determinants of health (including sex, systemic comorbidities, and other factors) in effectively and equitably deploying plasma AD biomarkers in the general population.

Plasma-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms: A community-based study.

INTRODUCTION: We examined associations between plasma-derived biomarkers of Alzheimer's disease (AD) and neuropsychiatric symptoms (NPS) in community-dwelling older adults. METHODS: Cross-sectional study involving 1005 persons ≥50 years of age (mean 74 years, 564 male, 118 cognitively impaired), who completed plasma-derived biomarker (amyloid beta 42 [Aß42]/Aß40, phosphorylated tau 181 [p-tau181], p-tau217, total tau [t-tau], neurofilament light [NfL]), and NPS assessment. RESULTS: P-tau181 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.41-3.00, p < 0.001), p-tau217 (OR 1.70, 95% CI 1.10-2.61, p = 0.016), and t-tau (OR 1.44, 95% CI 1.08-1.92, p = 0.012) were associated with appetite change. We also found that p-tau181 and p-tau217 were associated with increased symptoms of agitation (OR 1.93, 95% CI 1.20-3.11, p = 0.007 and OR 2.04, 95% CI 1.21-3.42, p = 0.007, respectively), and disinhibition (OR 2.39, 95% CI 1.45-3.93, p = 0.001 and OR 2.30, 95% CI 1.33-3.98, p = 0.003, respectively). Aß42/Aß40 and NfL were not associated with NPS. CONCLUSION: Higher plasma-derived p-tau181 and p-tau217 levels are associated with increased symptoms of appetite change, agitation, and disinhibition. These findings may support the validity of plasma tau biomarkers for predicting behavioral symptoms that often accompany cognitive impairment. HIGHLIGHTS: We studied 1005 community-dwelling persons aged ≥ 50 yearsHigher plasma tau levels are associated with increased neuropsychiatric symptomsAß42/Aß40 and NfL are not associated with neuropsychiatric symptomsClinicians should treat neuropsychiatric symptoms in persons with high plasma-derived tau.

Genetic risk scores enhance the diagnostic value of plasma biomarkers of brain amyloidosis.

Blood-based biomarkers offer strong potential to revolutionize diagnosis, trial enrolment and treatment monitoring in Alzheimer's disease (AD). However, further advances are needed before these biomarkers can achieve wider deployment beyond selective research studies and specialty memory clinics, including the development of frameworks for optimal interpretation of biomarker profiles. We hypothesized that integrating Alzheimer's disease genetic risk score (AD-GRS) data would enhance the diagnostic value of plasma AD biomarkers by better capturing extant disease heterogeneity. Analysing 962 individuals from a population-based sample, we observed that an AD-GRS was independently associated with amyloid PET levels (an early marker of AD pathophysiology) over and above APOE ε4 or plasma p-tau181, amyloid-ß42/40, glial fibrillary acidic protein or neurofilament light chain. Among individuals with a high or moderately high plasma p-tau181, integrating AD-GRS data significantly improved classification accuracy of amyloid PET positivity, including the finding that the combination of a high AD-GRS and high plasma p-tau181 outperformed p-tau181 alone in classifying amyloid PET positivity (88% versus 68%; P = 0.001). A machine learning approach incorporating plasma biomarkers, demographics and the AD-GRS was highly accurate in predicting amyloid PET levels (90% training set; 89% test set) and Shapley value analyses (an explainer method based in cooperative game theory) indicated that the AD-GRS and plasma biomarkers had differential importance in explaining amyloid deposition across individuals. Polygenic risk for AD dementia appears to account for a unique portion of disease heterogeneity, which could non-invasively enhance the interpretation of blood-based AD biomarker profiles in the population.

Plasma biomarkers for prediction of Alzheimer's disease neuropathologic change.

While plasma biomarkers for Alzheimer's disease (AD) are increasingly being evaluated for clinical diagnosis and prognosis, few population-based autopsy studies have evaluated their utility in the context of predicting neuropathological changes. Our goal was to investigate the utility of clinically available plasma markers in predicting Braak staging, neuritic plaque score, Thal phase, and overall AD neuropathological change (ADNC).We utilized a population-based prospective study of 350 participants with autopsy and antemortem plasma biomarker testing using clinically available antibody assay (Quanterix) consisting of Aß42/40 ratio, p-tau181, GFAP, and NfL. We utilized a variable selection procedure in cross-validated (CV) logistic regression models to identify the best set of plasma predictors along with demographic variables, and a subset of neuropsychological tests comprising the Mayo Clinic Preclinical Alzheimer Cognitive Composite (Mayo-PACC). ADNC was best predicted with plasma GFAP, NfL, p-tau181 biomarkers along with APOE ε4 carrier status and Mayo-PACC cognitive score (CV AUC = 0.798). Braak staging was best predicted using plasma GFAP, p-tau181, and cognitive scores (CV AUC = 0.774). Neuritic plaque score was best predicted using plasma Aß42/40 ratio, p-tau181, GFAP, and NfL biomarkers (CV AUC = 0.770). Thal phase was best predicted using GFAP, NfL, p-tau181, APOE ε4 carrier status and Mayo-PACC cognitive score (CV AUC = 0.754). We found that GFAP and p-tau provided non-overlapping information on both neuritic plaque and Braak stage scores whereas Aß42/40 and NfL were mainly useful for prediction of neuritic plaque scores. Separating participants by cognitive status improved predictive performance, particularly when plasma biomarkers were included. Plasma biomarkers can differentially inform about overall ADNC pathology, Braak staging, and neuritic plaque score when combined with demographics and cognitive variables and have significant utility for earlier detection of AD.

Identification, Measurement, and Assessment of the Clinical Utility of Human Pancreatic Polypeptide by Liquid Chromatography-Tandem Mass Spectrometry.

Human pancreatic polypeptide (HPP) is a 36 amino acid peptide hormone that plays a role in the bidirectional communication between the digestive system and the brain. HPP measurements are used to assess vagal nerve function following sham feeding and to detect gastroenteropancreatic-neuroendocrine tumors. These tests have historically been conducted by radioimmunoassays, but liquid chromatography-tandem mass spectrometry (LC-MS/MS) has several advantages such as improved specificity and elimination of radioactive molecules. Here, we present our LC-MS/MS method. Initially, samples were immunopurified and subjected to LC-high resolution accurate mass tandem mass spectrometry (HRAM-MS/MS) to identify circulating forms of the peptide in human plasma. We identified 23 forms of HPP, including several glycosylated forms. The most abundant peptides then were used for targeted LC-MS/MS measurements. LC-MS/MS performance for precision, accuracy, linearity, recovery, limit of detection, and carryover met our acceptance criteria based on CLIA regulations. Additionally, we observed the expected physiological rise in HPP in response to sham feeding. Our results indicate that HPP measurement by LC-MS/MS produces clinically equivalent results to our established immunoassay when several peptides are monitored, making it a suitable replacement. The measurement of peptide fragments, including modified species, might have additional clinical value.

Associations of Neurodegeneration Biomarkers in Cerebrospinal Fluid with Markers of Alzheimer's Disease and Vascular Pathology.

BACKGROUND: The National Institute on Aging-Alzheimer's Association Research Framework proposes defining Alzheimer's disease by grouping imaging and fluid biomarkers by their respective pathologic processes. The AT(N) structure proposes several neurodegenerative fluid biomarkers (N) including total tau (t-tau), neurogranin (Ng), and neurofilament light chain (NfL). However, pathologic drivers influencing each biomarker remain unclear. OBJECTIVE: To determine whether cerebrospinal fluid (CSF)-neurodegenerative biomarkers (N) map differentially to Alzheimer's disease pathology measured by Aß42 (an indicator of amyloidosis, [A]), p-tau (an indicator of tau deposition, [T]), and MRI vascular pathology indicators (measured by white-matter integrity, infarcts, and microbleeds [V]). METHODS: Participants were from Mayo Clinic Study of Aging (MCSA) with CSF measures of NfL, Ng, t-tau, Aß42, and p-tau and available MRI brain imaging. Linear models assessed associations between CSF neurodegeneration (N) markers, amyloid markers (A), tau (T), and vascular pathology (V). RESULTS: Participants (n = 408) had a mean age of 69.2±10.7; male, 217 (53.2%); cognitively unimpaired, 359 (88%). All three neurodegeneration biomarkers correlated with age (p < 0.001 for NfL and t-tau, p = 0.018 for Ng). Men had higher CSF-NfL levels; women had higher Ng (p < 0.001). NfL and t-tau levels correlated with infarcts (p = 0.009, p = 0.034 respectively); no biomarkers correlated with white-matter integrity. N biomarkers correlated with p-tau levels (T, p < 0.001). Higher Aß42 levels associated with higher N-biomarker levels but only among cognitively unimpaired (A, p < 0.001). CONCLUSION: The influence of vascular pathology in the general population on CSF (N) biomarkers is modest, with greater influence of infarcts than white-matter disruption. Neurodegeneration markers more closely correlated with tau than amyloid markers.

Predicting amyloid PET and tau PET stages with plasma biomarkers.

Staging the severity of Alzheimer's disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid and tau PET has face validity; however, this would be more practical with plasma biomarkers. Our objectives were, first, to examine approaches for staging amyloid and tau PET and, second, to examine prediction of amyloid and tau PET stages using plasma biomarkers. Participants (n = 1136) were enrolled in either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center; had a concurrent amyloid PET, tau PET and blood draw; and met clinical criteria for cognitively unimpaired (n = 864), mild cognitive impairment (n = 148) or Alzheimer's clinical syndrome with dementia (n = 124). The latter two groups were combined into a cognitively impaired group (n = 272). We used multinomial regression models to estimate discrimination [concordance (C) statistics] among three amyloid PET stages (low, intermediate, high), four tau PET stages (Braak 0, 1-2, 3-4, 5-6) and a combined amyloid and tau PET stage (none/low versus intermediate/high severity) using plasma biomarkers as predictors separately within unimpaired and impaired individuals. Plasma analytes, p-tau181, Aß1-42 and Aß1-40 (analysed as the Aß42/Aß40 ratio), glial fibrillary acidic protein and neurofilament light chain were measured on the HD-X Simoa Quanterix platform. Plasma p-tau217 was also measured in a subset (n = 355) of cognitively unimpaired participants using the Lilly Meso Scale Discovery assay. Models with all Quanterix plasma analytes along with risk factors (age, sex and APOE) most often provided the best discrimination among amyloid PET stages (C = 0.78-0.82). Models with p-tau181 provided similar discrimination of tau PET stages to models with all four plasma analytes (C = 0.72-0.85 versus C = 0.73-0.86). Discriminating a PET proxy of intermediate/high from none/low Alzheimer's disease neuropathological change with all four Quanterix plasma analytes was excellent but not better than p-tau181 only (C = 0.88 versus 0.87 for unimpaired and C = 0.91 versus 0.90 for impaired). Lilly p-tau217 outperformed the Quanterix p-tau181 assay for discriminating high versus intermediate amyloid (C = 0.85 versus 0.74) but did not improve over a model with all Quanterix plasma analytes and risk factors (C = 0.85 versus 0.83). Plasma analytes along with risk factors can discriminate between amyloid and tau PET stages and between a PET surrogate for intermediate/high versus none/low neuropathological change with accuracy in the acceptable to excellent range. Combinations of plasma analytes are better than single analytes for many staging predictions with the exception that Quanterix p-tau181 alone usually performed equivalently to combinations of Quanterix analytes for tau PET discrimination.