Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease–Related β-Amyloid Status
Open accessAbstract
IMPORTANCE: Accurate blood-based biomarkers for Alzheimer disease (AD) might improve the diagnostic accuracy in primary care, referrals to memory clinics, and screenings for AD trials. OBJECTIVE: To examine the accuracy of plasma β-amyloid (Aβ) and tau measured using fully automated assays together with other blood-based biomarkers to detect cerebral Aβ. DESIGN, SETTING, AND PARTICIPANTS: Two prospective, cross-sectional, multicenter studies. Study participants were consecutively enrolled between July 6, 2009, and February 11, 2015 (cohort 1), and between January 29, 2000, and October 11, 2006 (cohort 2). Data were analyzed in 2018. The first cohort comprised 842 participants (513 cognitively unimpaired [CU], 265 with mild cognitive impairment [MCI], and 64 with AD dementia) from the Swedish BioFINDER study. The validation cohort comprised 237 participants (34 CU, 109 MCI, and 94 AD dementia) from a German biomarker study. MAIN OUTCOME AND MEASURES: The cerebrospinal fluid (CSF) Aβ42/Aβ40 ratio was used as the reference standard for brain Aβ status. Plasma Aβ42, Aβ40 and tau were measured using Elecsys immunoassays (Roche Diagnostics) and examined as predictors of Aβ status in logistic regression models in cohort 1 and replicated in cohort 2. Plasma neurofilament light chain (NFL) and heavy chain (NFH) and APOE genotype were also examined in cohort 1. RESULTS: The mean (SD) age of the 842 participants in cohort 1 was 72 (5.6) years, with a range of 59 to 88 years, and 446 (52.5%) were female. For the 237 in cohort 2, mean (SD) age was 66 (10) years with a range of 23 to 85 years, and 120 (50.6%) were female. In cohort 1, plasma Aβ42 and Aβ40 predicted Aβ status with an area under the receiver operating characteristic curve (AUC) of 0.80 (95% CI, 0.77-0.83). When adding APOE, the AUC increased significantly to 0.85 (95% CI, 0.82-0.88). Slight improvements were seen when adding plasma tau (AUC, 0.86; 95% CI, 0.83-0.88) or tau and NFL (AUC, 0.87; 95% CI, 0.84-0.89) to Aβ42, Aβ40 and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants. Applying the plasma Aβ42 and Aβ40 model from cohort 1 in cohort 2 resulted in slightly higher AUC (0.86; 95% CI, 0.81-0.91), but plasma tau did not contribute. Using plasma Aβ42, Aβ40, and APOE in an AD trial screening scenario reduced positron emission tomography costs up to 30% to 50% depending on cutoff. CONCLUSIONS AND RELEVANCE: Plasma Aβ42 and Aβ40 measured using Elecsys immunoassays predict Aβ status in all stages of AD with similar accuracy in a validation cohort. Their accuracy can be further increased by analyzing APOE genotype. Potential future applications of these blood tests include prescreening of Aβ positivity in clinical AD trials to lower the costs and number of positron emission tomography scans or lumbar punctures.
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TL;DR
In two cross-sectional cohorts, fully automated Elecsys plasma Aβ42/Aβ40 and separate Aβ42/Aβ40 models predicted cerebral Aβ status with AUCs of 0.77–0.86, and APOE genotype improved accuracy. These blood-based assays may serve as prescreening tools to reduce PET/CSF testing, though accuracy alone is not sufficient for clinical use.
Key findings
- In BioFINDER (n = 842), plasma Aβ42/Aβ40 ratio predicted Aβ positivity with an AUC of 0.77 (95% CI, 0.74–0.81); using Aβ42 and Aβ40 as separate predictors improved the AUC to 0.80 (95% CI, 0.77–0.83; P = .01; ΔAIC, –66).
- Adding APOE genotype to plasma Aβ42 and Aβ40 increased the AUC significantly from 0.80 to 0.85 (95% CI, 0.82–0.88; P < .001); adding tau then NFL raised the AUC to 0.86 and 0.87, respectively.
- In the independent validation cohort (n = 237), applying the BioFINDER Aβ42 + Aβ40 model yielded an AUC of 0.86 (95% CI, 0.81–0.91); adding tau yielded an AUC of 0.84 (95% CI, 0.79–0.89). At BioFINDER-derived cutoffs, Aβ42/Aβ40 had sensitivity 75% and specificity 72% in BioFINDER and 70%/73% in validation; Aβ42 + Aβ40 had 73%/76% and 89%/69%, respectively.
- In a cost-benefit scenario for 1000 Aβ-positive trial participants and $4000 per Aβ PET, using plasma Aβ42, Aβ40, and APOE at the highest Youden cutoff reduced PET scans by approximately 800 and lowered PET costs by approximately $3.2 million (from a total of approximately $9.2 million).
Methods
- Two cross-sectional studies: BioFINDER enrolled participants from July 6, 2009, to February 11, 2015, in southern Sweden; after exclusions, 842 participants were included (513 cognitively unimpaired, 265 mild cognitive impairment, 64 AD dementia). The independent validation cohort included 237 participants from Ulm and Hannover, Germany (34 CU, 109 MCI, 94 AD mild dementia).
- Plasma Aβ42, Aβ40, and tau were measured with fully automated Elecsys immunoassays on a cobas e 601 analyzer; Aβ status was defined by CSF Aβ42/Aβ40 < 0.059, with a secondary reference standard of CSF P-tau/Aβ42 ≥ 0.022. APOE genotype and plasma NFL/NFH were also examined in BioFINDER.
- Logistic regression models were built in BioFINDER using AIC for model selection, with AUC/ROC and DeLong statistics for comparisons; BioFINDER model estimates and intercepts were applied to the validation cohort.
Limitations
- Paper-stated: the validation analysis lacked APOE data, plasma tau did not improve the replicated model, and the smaller validation population prevented subpopulation analyses. The authors also state that overall Aβ42/Aβ40 accuracy is not sufficient as a stand-alone clinical test and that further studies are needed in lower-prevalence primary care settings and more heterogeneous dementia cohorts.
- Text-evident: the study design is cross-sectional; in BioFINDER all AD dementia participants were Aβ positive by definition, so AD could not be examined separately using Aβ status as outcome; 101 plasma NFH measurements were below the assay detection limit.
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0 of 43 cited sources checked · 0 supported · 0 flagged
- Findingown data
In the validation cohort, the combination of plasma Aβ42 and Aβ40 had a sensitivity of 89% and specificity of 69% for Aβ status.
“Aβ42, Aβ40 | 0.45 | 89 (80-95) | 69 (54-81)”
Quote in the paperSubstantial claim - Findingown data
In the validation cohort, the combination of plasma Aβ42, Aβ40, and tau had a sensitivity of 89% and specificity of 64% for Aβ status.
“Aβ42, Aβ40, tau | 0.36 | 89 (74-94) | 64 (49-74)”
Quote in the paperSubstantial claim - Findingown data
In the validation cohort, applying the BioFINDER model that included plasma Aβ42, Aβ40, and tau gave a slightly lower AUC (0.84; 95% CI, 79-89) than using only plasma Aβ42 and Aβ40.
“When applying the BioFINDER model that included plasma Aβ42, Aβ40, and tau in the validation cohort, the AUC was slightly lower than when using only plasma Aβ42 and Aβ40 (AUC, 0.84; 95% CI, 79-89).”
Quote in the paperNot a substantial claim - Findingown data
In the BioFINDER cohort, the combination of plasma Aβ42, Aβ40, tau, NFL, and APOE had a sensitivity of 73% and specificity of 86% for Aβ status.
“Aβ42, Aβ40, tau, NFL, APOE | 0.52 | 73 (64-78) | 86 (77-89)”
Quote in the paperSubstantial claim - Findingown data
When comparing Aβ groups stratified by diagnostic subgroup, plasma levels of Aβ42 were lower in CU Aβ-positive, MCI Aβ-positive and AD Aβ-positive dementia groups compared with CU Aβ-negative and MCI Aβ-negative groups.
“When comparing Aβ groups stratified by diagnostic subgroup, plasma levels of Aβ42 were lower in the CU Aβ-positive, MCI Aβ-positive and AD Aβ-positive dementia groups compared with the CU Aβ-negative and MCI Aβ-negative groups (P < .001 for all; Figure 1D).”
Quote in the paperSubstantial claim
- Findingown data
Adding plasma tau to plasma Aβ42 and Aβ40 increased the AUC nonsignificantly to 0.81 (95% CI, 0.78-0.84).
“When adding plasma tau, AUC increased nonsignificantly to 0.81 (95% CI, 0.78-0.84) and further improved the model fit (ΔAIC, –27).”
Quote in the paperNot a substantial claim - Findingown data
Adding plasma NFL to plasma Aβ42, Aβ40, tau, and APOE further slightly increased the AUC to 0.87 (95% CI, 0.84-0.89; ΔAIC -16).
“A further slight increase was seen when adding plasma NFL to plasma Aβ42, Aβ40, tau, and APOE (AUC, 0.87; 95% CI, 0.84-0.89; ΔAIC –16; Figure 2A-B).”
Quote in the paperNot a substantial claim - Findingown data
In the validation cohort, the plasma Aβ42/Aβ40 ratio had a sensitivity of 70% and specificity of 73% for Aβ status.
“Aβ42/Aβ40 ratio | 0.065 | 70 (61-80) | 73 (61-81)”
Quote in the paperSubstantial claim - Findingown data
In the BioFINDER cohort, the combination of plasma Aβ42, Aβ40, and APOE had a sensitivity of 88% and specificity of 68% for Aβ status.
“Aβ42, Aβ40, APOE | 0.29 | 88 (82-92) | 68 (58-72)”
Quote in the paperSubstantial claim - Findingown data
In the BioFINDER cohort, the plasma Aβ42/Aβ40 ratio had a sensitivity of 75% and specificity of 72% for Aβ status.
“Aβ42/Aβ40 ratio | 0.065 | 75 (68-80) | 72 (65-77)”
Quote in the paperSubstantial claim - Findingown data
Plasma Aβ40 levels were lower in the AD Aβ-positive dementia group compared with all other groups.
“Plasma Aβ40 levels were lower in the AD Aβ-positive dementia group compared with all other groups (P < .001 for all), but there were no differences between CU Aβ-negative, CU Aβ-positive, and MCI Aβ-positive participants (Figure 1E).”
Quote in the paperNot a substantial claim - Findingown data
Adding plasma tau to plasma Aβ42, Aβ40, and APOE increased the AUC slightly to 0.86 (95% CI, 0.83-0.88; ΔAIC, -20).
“Adding plasma tau to plasma Aβ42, Aβ40, and APOE increased the AUC slightly to 0.86 (95% CI, 0.83-0.88; ΔAIC, –20).”
Quote in the paperNot a substantial claim - Findingown data
Plasma Aβ42/Aβ40 ratio, measured using immunoassay, accurately predicted cerebral Aβ status in all stages of Alzheimer disease in the BioFINDER cohort (n = 842) and in an independent validation cohort (n = 237).
“In 2 cross-sectional studies, plasma β-amyloid 42 to β-amyloid 40 ratio, measured using immunoassay, accurately predicted cerebral β-amyloid status in all stages of Alzheimer disease in the BioFINDER cohort (n = 842) and in an independent validation cohort (n = 237).”
Quote in the paperSubstantial claim - Findingown data
In the BioFINDER cohort, the combination of plasma Aβ42, Aβ40, and tau had a sensitivity of 86% and specificity of 68% for Aβ status.
“Aβ42, Aβ40, tau | 0.36 | 86 (78-90) | 68 (61-72)”
Quote in the paperSubstantial claim - Findingown data
Adding APOE genotype to plasma Aβ42 and Aβ40 increased the AUC significantly from 0.80 to 0.85 (95% CI, 0.82-0.88; P < .001).
“However, when instead adding APOE genotype to plasma Aβ42 and Aβ40, AUC increased significantly from 0.80 to 0.85 (95% CI, 0.82-0.88; P < .001; Figure 2A-B; eTable 4 in the Supplement).”
- Also stated in: § Discussion · plain
“The addition of APOE genotype increased the AUC significantly to 0.85 (Figure 2A and B).”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
In the BioFINDER cohort, the combination of plasma Aβ42 and Aβ40 had a sensitivity of 73% and specificity of 76% for Aβ status.
“Aβ42, Aβ40 | 0.45 | 73 (65-78) | 76 (68-80)”
Quote in the paperSubstantial claim - Findingown data
The diagnostic accuracy was further increased by analyzing APOE genotype.
“The diagnostic accuracy was further increased by analyzing APOE genotype.”
Quote in the paperSubstantial claim - Findingown data
The decrease in plasma Aβ42 was more pronounced in AD Aβ-positive dementia compared with CU Aβ-positive and MCI Aβ-positive groups.
“The decrease in plasma Aβ42 was more pronounced in AD Aβ-positive dementia compared with CU Aβ-positive and MCI Aβ positive groups.”
Quote in the paperNot a substantial claim - Findingown data
Plasma tau and NFL had a slight effect on accuracy (AUC, +0.01 to 0.02).
“Plasma tau and NFL had a slight effect on the accuracy (AUC, +0.01 to 0.02; Figure 2A and B).”
Quote in the paperNot a substantial claim - Findingown data
The correlations between plasma and corresponding CSF biomarkers were similar within diagnostic subgroups.
“The correlations were similar within diagnostic subgroups (eFigure 1 and eTable 3 in the Supplement).”
Quote in the paperNot a substantial claim - Findingown data
The plasma Aβ42/Aβ40 ratio predicted Aβ positivity with an AUC of 0.77 (95% CI, 0.74-0.81) in the whole BioFINDER population.
“The plasma Aβ42/Aβ40 ratio predicted Aβ positivity with an AUC of 0.77 (95% CI, 0.74-0.81) in the whole BioFINDER population.”
Quote in the paperSubstantial claim - Findingown data
There were no differences in the plasma Aβ42/Aβ40 ratio across Aβ-positive groups.
“The plasma Aβ42/Aβ40 ratio was lower in the CU Aβ-positive, MCI Aβ-positive, and AD Aβ-positive dementia groups than in the CU Aβ-negative and MCI Aβ-negative groups with no differences across the Aβ-positive groups (Figure 1F).”
Quote in the paperSubstantial claim - Findingown data
There were no differences in plasma Aβ40 levels between CU Aβ-negative, CU Aβ-positive, and MCI Aβ-positive participants.
“Plasma Aβ40 levels were lower in the AD Aβ-positive dementia group compared with all other groups (P < .001 for all), but there were no differences between CU Aβ-negative, CU Aβ-positive, and MCI Aβ-positive participants (Figure 1E).”
Quote in the paperSubstantial claim - Findingown data
In 842 participants, plasma Aβ42 and Aβ40 using the fully automated Elecsys platform detected abnormal levels of Aβ in the brain with an AUC of 0.80.
“In this study of 842 participants, we found that plasma Aβ42 and Aβ40 using the fully automated Elecsys platform detected abnormal levels of Aβ in the brain with an AUC of 0.80 (Figure 2A and B).”
Quote in the paperSubstantial claim - Findingown data
Plasma NFH did not contribute to Aβ prediction in addition to plasma Aβ42 and Aβ40.
“Plasma NFH did not contribute to Aβ prediction in addition to plasma Aβ42 and Aβ40 (eTable 5 in the Supplement).”
Quote in the paperNot a substantial claim - Findingown data
Adding plasma tau to plasma Aβ42 and Aβ40 improved the model fit (ΔAIC, -27).
“When adding plasma tau, AUC increased nonsignificantly to 0.81 (95% CI, 0.78-0.84) and further improved the model fit (ΔAIC, –27).”
Quote in the paperNot a substantial claim - Findingown data
The plasma Aβ42/Aβ40 ratio was lower in CU Aβ-positive, MCI Aβ-positive, and AD Aβ-positive dementia groups than in CU Aβ-negative and MCI Aβ-negative groups.
“The plasma Aβ42/Aβ40 ratio was lower in the CU Aβ-positive, MCI Aβ-positive, and AD Aβ-positive dementia groups than in the CU Aβ-negative and MCI Aβ-negative groups with no differences across the Aβ-positive groups (Figure 1F).”
Quote in the paperSubstantial claim - Findingown data
Results were similar when the CSF P-tau/Aβ42 ratio was used to define Aβ positivity.
“The results were also similar when the CSF P-tau/Aβ42 ratio was used to define Aβ positivity (eFigure 3 in the Supplement).”
Quote in the paperNot a substantial claim - Findingown data
In BioFINDER, plasma levels of Aβ42, Aβ40, and Aβ42/Aβ40 were decreased in Aβ-positive compared with Aβ-negative participants.
“In BioFINDER, plasma levels of Aβ42, Aβ40, and Aβ42/Aβ40 were decreased in Aβ-positive (CSF Aβ42/Aβ40 ≤ 0.059) compared with Aβ-negative (CSF Aβ42/Aβ40 > 0.059) participants (Aβ42, P < .001; Aβ40 P = .003, Aβ42/Aβ42, P < .001; Figure 1A-C).”
Quote in the paperSubstantial claim - Findingown data
In the whole BioFINDER population, there were statistically significant positive correlations between all plasma and corresponding CSF biomarkers.
“In the whole BioFINDER population, there were statistically significant positive correlations between all plasma and corresponding CSF biomarkers (eTable 3 in the Supplement).”
Quote in the paperSubstantial claim - Findingown data
101 plasma NFH measurements were below the detection limit of the assays.
“However, 101 plasma NFH measurements were below the detection limit of the assays, and development of more sensitive plasma NFH assays is thus warranted to establish whether this biomarker could further improve the diagnostic performance of plasma Aβ.”
Quote in the paperSubstantial claim - Findingcitation
Blood biomarkers can lower the costs for examinations up to 30% to 50% depending on the cutoff.
“Another useful setting for the blood biomarkers are clinical AD trials enrolling Aβ-positive participants, where they can be used for prescreening to minimize the number of unnecessary (Aβ-negative) lumbar punctures and Aβ PET scans, as well as lowering the costs for the examinations up to 30% to 50% depending on the cutoff (eFigure 5 in the Supplement).48”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Palmqvist S, Insel PS, Zetterberg H,; Alzheimer’s Disease Neuroimaging Initiative; Swedish BioFINDER study Accurate risk estimation of β-amyloid positivity to identify prodromal Alzheimer’s disease: cross-validation study of practical algorithms. Alzheimers Dement. 2019; 15(2): 194- 204. doi: 10.1016/j.jalz.2018.08.014 30365928 PMC6374284
Not checked in the free run.
- Rests on an assumption: There is an ongoing great need to recruit large cohorts for AD drug trials in preclinical and prodromal stages.
- Findingown data
The Aβ assays perform similarly in CU populations with lower prevalence of Aβ positivity (29%).
“In the present study, we showed that the Aβ assays perform similarly in CU populations with lower prevalence of Aβ positivity (Figure 3A and B; Aβ-positive prevalence, 29%).”
Quote in the paperNot a substantial claim - Findingcitation
Accuracies were similar in different subsamples including CU and younger participants.
“The latter was, however, tested in BioFINDER and the accuracies were similar in different subsamples including CU (Figure 3A and B) and younger participants (Figure 3E and F) where Aβ positivity might be more difficult to identify using alternative methods such as cognitive testing and age stratification.40”
Quote in the paperNot a substantial claim - Premisecitation
Two independent groups demonstrated improved accuracy for plasma Aβ42/Aβ40 using immunoprecipitation-mass spectrometry assays.
“Most recently, 2 independent groups demonstrated improved accuracy for plasma Aβ42/Aβ40 using immunoprecipitation–mass spectrometry assays.19,20”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [19] Nakamura A, Kaneko N, Villemagne VL, High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018; 554(7691): 249- 254. doi: 10.1038/nature25456 29420472 source
Not checked in the free run.
- cites [20] Ovod V, Ramsey KN, Mawuenyega KG, Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017; 13(8): 841- 849. doi: 10.1016/j.jalz.2017.06.2266 28734653 PMC5567785 source
Not checked in the free run.
- Study design and conductown data
The cutoff of CSF Aβ42/Aβ40 of less than 0.059 established in BioFINDER to define Aβ positivity was also used in the validation cohort after a thorough assessment of the CSF Aβ42/Aβ40 distribution.
“The cutoff of CSF Aβ42/Aβ40 of less than 0.059 established in BioFINDER to define Aβ positivity was also used in the validation cohort after a thorough assessment of the CSF Aβ42/Aβ40 distribution.”
Quote in the paperSubstantial claim - Premisecitation
Fully automated immunoassays have been developed by several different vendors with improved reliability and precision for CSF Aβ and tau species.
“Recently, fully automated immunoassays have been developed by several different vendors with improved reliability and precision for CSF Aβ and tau species.23,24,25”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [23] Bittner T, Zetterberg H, Teunissen CE, Technical performance of a novel, fully automated electrochemiluminescence immunoassay for the quantitation of β-amyloid (1-42) in human cerebrospinal fluid. Alzheimers Dement. 2016; 12(5): 517- 526. doi: 10.1016/j.jalz.2015.09.009 26555316 source
Not checked in the free run.
- cites [24] Hansson O, Seibyl J, Stomrud E,; Swedish BioFINDER study group; Alzheimer’s Disease Neuroimaging Initiative CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018; 14(11): 1470- 1481. doi: 10.1016/j.jalz.2018.01.010 29499171 PMC6119541 source
Not checked in the free run.
- cites [25] Janelidze S, Pannee J, Mikulskis A, Concordance between different amyloid immunoassays and visual amyloid positron emission tomographic assessment. JAMA Neurol. 2017; 74(12): 1492- 1501. doi: 10.1001/jamaneurol.2017.2814 29114726 PMC5822196 source
Not checked in the free run.
- Interpretationown data
The accuracies of the Aβ42 and Aβ40 assays are not sufficient to be used on their own as a clinical test of Aβ positivity.
“Overall, the accuracies of the Aβ42 and Aβ40 assays are not sufficient to be used on their own as a clinical test of Aβ positivity; additional assay development is needed before this can be recommended, possibly together with other blood biomarkers and screening tools in diagnostic algorithms.”
Quote in the paperSubstantial claim - Interpretationcitation
The contribution of plasma tau to plasma Aβ42/Aβ40 is clinically not comparable with the contribution of CSF tau combined with CSF Aβ42.
“Plasma tau increased the AUC slightly, and provided a better model fit (ΔAIC –27), but clinically this is not comparable with the contribution CSF tau has combined with CSF Aβ42,24 and improved plasma tau assays are probably needed in the future, such as measurement of specifically phosphorylated tau,46 to increase the added value of plasma tau to plasma Aβ42 and Aβ40.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Hansson O, Seibyl J, Stomrud E,; Swedish BioFINDER study group; Alzheimer’s Disease Neuroimaging Initiative CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018; 14(11): 1470- 1481. doi: 10.1016/j.jalz.2018.01.010 29499171 PMC6119541 source
Not checked in the free run.
- Premisecitation
Plasma and CSF NFL show relatively high correlations.
“Despite the present and previous results showing relatively high correlations between plasma and CSF NFL (eTable 3 in the Supplement and the study by Hansson et al47), we saw a modest increase in accuracy in addition to plasma Aβ42 and Aβ40 (Figure 2; eTable 4 in the Supplement).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hansson et al47
Not checked in the free run.
- Premisecitation
Two recent mass spectrometry-based studies provided overall better accuracies for plasma Aβ42/Aβ40 (AUC, 0.84-0.97 depending on population and reference standard).
“In mass spectrometry–based techniques, 2 recent studies have provided overall better accuracies for plasma Aβ42/Aβ40 (AUC, 0.84-0.97 depending on population and reference standard).19,20”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [19] Nakamura A, Kaneko N, Villemagne VL, High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018; 554(7691): 249- 254. doi: 10.1038/nature25456 29420472 source
Not checked in the free run.
- cites [20] Ovod V, Ramsey KN, Mawuenyega KG, Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017; 13(8): 841- 849. doi: 10.1016/j.jalz.2017.06.2266 28734653 PMC5567785 source
Not checked in the free run.
- Interpretationown data
The generalizability of the BioFINDER results has already been shown in the present study where the plasma Aβ42 and Aβ40 model established in BioFINDER could be applied in the independent validation cohort with better accuracy (AUC, 0.86 vs 0.80).
“To some extent, the generalizability of the BioFINDER results has already been shown in the present study where the plasma Aβ42 and Aβ40 model established in BioFINDER could be applied in the independent validation cohort with better accuracy (AUC, 0.86 vs 0.80; Figure 2).”
Quote in the paperSubstantial claim
- May combine two claims. 20
- Classified as probably not a substantial claim. 9
May combine two claims.
Findingown dataUsing the highest Youden index cutoff for plasma Aβ42, Aβ40, and APOE reduces the number of PET scans by approximately 800 and lowers PET costs by approximately $3.2 million (from a total cost of approximately $9.2 million).
“For example, using the highest Youden index cutoff (Table 2) for plasma Aβ42, Aβ40, and APOE reduces the number of PET scans by approximately 800 and lowers the PET costs by approximately $3.2 million (from a total cost of approximately $9.2 million).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWith the alternative reference standard CSF P-tau/Aβ42 ≥ 0.022, the accuracy for plasma Aβ42 and Aβ40 was slightly lower (AUC, 0.83; 95% CI, 0.78-0.89) but still better than the corresponding BioFINDER results (AUC, 0.79; 95% CI, 0.76-0.82).
“With the alternative reference standard for Aβ status (CSF P-tau/Aβ42 ≥ 0.022; eFigure 4 in the Supplement), the accuracy was slightly lower for plasma Aβ42 and Aβ40 (AUC, 0.83; 95% CI, 0.78-0.89) but still better than the corresponding results in the BioFINDER cohort (AUC, 0.79; 95% CI, 0.76-0.82; eFigure 3 in the Supplement).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe accuracy of the biomarkers was similar in different age groups and in those with and without cognitive impairment (AUC ±0.02 compared with the total population).
“We also tested the accuracy of the biomarkers in different age groups and in those with and without cognitive impairment (Figure 3; eTable 4 and eTable 6 in the Supplement), with similar results (AUC ±0.02 compared with the total population).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the independent validation cohort (n = 237), the AUC for plasma Aβ42 and Aβ40 to predict Aβ positivity was 0.86 (95% CI, 0.81-0.91) when applying the BioFINDER model, compared with 0.80 (95% CI, 0.77-0.83) in BioFINDER.
“The AUC for plasma Aβ42 and Aβ40 to predict Aβ positivity was 0.86 (95% CI, 0.81-0.91) when applying the estimates from the model established in BioFINDER (compared with an AUC of 0.80, 95% CI 0.77-0.83 in BioFINDER).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataUsing plasma Aβ42 and Aβ40 as separate predictors in a logistic regression resulted in a slightly but significantly better AUC (0.80; 95% CI, 0.77-0.83; P = .01) and a better model fit (ΔAIC, -66) than the plasma Aβ42/Aβ40 ratio.
“Using plasma Aβ42 and Aβ40 as separate predictors in a logistic regression resulted in a slightly but significantly better AUC (0.80; 95% CI, 0.77-0.83; P = .01) and a better model fit (ΔAIC, –66).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn CU and cognitively impaired participants, results were similar, except that plasma tau and NFL were not significant predictors in the cognitively impaired group.
“The results were similar in CU and cognitively impaired participants, respectively, except that plasma tau and NFL were not a significant predictor in the cognitively impaired group (eTable 4 in the Supplement).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataUsing Aβ40 as a separate predictor instead of the fixed Aβ42/Aβ40 ratio improved both model fit and accuracy (AUC 0.77 vs 0.80; P = .01; ΔAIC -66).
“We found that instead of using the fixed ratio of Aβ42/Aβ40, both the model fit (AIC) and accuracy (AUC) were slightly but significantly improved when the model was adjusted for Aβ40 concentrations independent of Aβ42 (ie, used as a separate predictor in the logistic regression models) (AUC 0.77 vs 0.80; P = .01; ΔAIC –66; eTable 4 in the Supplement).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCompared with plasma tau and NFL, plasma NFH had a poorer performance and did not improve accuracy.
“Compared with plasma tau and NFL, plasma NFH had a poorer performance and did not improve accuracy (eTable 5 in the Supplement).”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitationβ-Amyloid status was determined using the Elecsys CSF Aβ42/Aβ40 ratio, which has been validated against amyloid PET status with more than 90% agreement.
“β-Amyloid status was determined using the Elecsys CSF Aβ42/Aβ40 ratio, which is a ratio that has been validated against amyloid PET status with more than 90% agreement.32,33,34”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [32] Janelidze S, Zetterberg H, Mattsson N,; Swedish BioFINDER study group CSF Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer disease. Ann Clin Transl Neurol. 2016; 3(3): 154- 165. doi: 10.1002/acn3.274 27042676 PMC4774260
Not checked in the free run.
- cites [33] Leuzy A, Chiotis K, Hasselbalch SG, Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study. Brain. 2016; 139(Pt 9): 2540- 2553. doi: 10.1093/brain/aww160 27401520 PMC4995359
Not checked in the free run.
- cites [34] Lewczuk P, Matzen A, Blennow K, Cerebrospinal fluid Aβ42/40 corresponds better than Aβ42 to amyloid PET in Alzheimer’s disease. J Alzheimers Dis. 2017; 55(2): 813- 822. doi: 10.3233/JAD-160722 27792012 PMC5147502
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductnone givenThe validation cohort is independent.
“For the independent validation cohort, the study was approved by the ethical committee of the Medizinische Hochschule in Hannover and the ethical committee of the University of Ulm, and all participants gave written informed consent.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationMany candidate blood biomarkers have failed in replication studies, but somewhat promising results have been seen for plasma tau, NFL, and combinations of Aβ42 and Aβ40.
“Many candidate blood biomarkers have failed in replication studies,7,8 but somewhat promising results have been seen for plasma tau, neurofilament light chain (NFL), and combinations of Aβ42 and Aβ40.9,10,11,12,13,14,15,16,17”
Quote in the paperSubstantial claim0 of 10 sources checked- cites [7] Keshavan A, Heslegrave A, Zetterberg H, Schott JM Blood biomarkers for Alzheimer’s disease: much promise, cautious progress. Mol Diagn Ther. 2017; 21(1): 13- 22. doi: 10.1007/s40291-016-0241-0 27738910
Not checked in the free run.
- cites [8] Voyle N, Baker D, Burnham SC,; AIBL research group Blood protein markers of neocortical amyloid-β burden: a candidate study using SOMAscan technology. J Alzheimers Dis. 2015; 46(4): 947- 961. doi: 10.3233/JAD-150020 25881911 PMC4923714
Not checked in the free run.
- cites [9] Chatterjee P, Goozee K, Sohrabi HR, Association of plasma neurofilament light chain with neocortical amyloid-β load and cognitive performance in cognitively normal elderly participants. J Alzheimers Dis. 2018; 63(2): 479- 487. doi: 10.3233/JAD-180025 29630554
Not checked in the free run.
- cites [10] Dage JL, Wennberg AMV, Airey DC, Levels of tau protein in plasma are associated with neurodegeneration and cognitive function in a population-based elderly cohort. Alzheimers Dement. 2016; 12(12): 1226- 1234. doi: 10.1016/j.jalz.2016.06.001 27436677 PMC5148697 source
Not checked in the free run.
- cites [11] Deters KD, Risacher SL, Kim S,; Alzheimer Disease Neuroimaging Initiative Plasma tau association with brain atrophy in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis. 2017; 58(4): 1245- 1254. doi: 10.3233/JAD-161114 28550246 PMC5523909
Not checked in the free run.
- cites [12] Fandos N, Pérez-Grijalba V, Pesini P,; AIBL Research Group Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals. Alzheimers Dement (Amst). 2017; 8: 179- 187. 28948206 PMC5602863 source
Not checked in the free run.
- cites [13] Janelidze S, Stomrud E, Palmqvist S, Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci Rep. 2016; 6: 26801. doi: 10.1038/srep26801 27241045 PMC4886210 source
Not checked in the free run.
- cites [14] Lue LF, Sabbagh MN, Chiu MJ, Plasma levels of Aβ42 and tau identified probable Alzheimer’s dementia: findings in two cohorts. Front Aging Neurosci. 2017; 9: 226. doi: 10.3389/fnagi.2017.00226 28790911 PMC5522888
Not checked in the free run.
- cites [15] Mattsson N, Andreasson U, Zetterberg H, Blennow K; Alzheimer’s Disease Neuroimaging Initiative Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 2017; 74(5): 557- 566. doi: 10.1001/jamaneurol.2016.6117 28346578 PMC5822204 source
Not checked in the free run.
- cites [16] Mattsson N, Zetterberg H, Janelidze S,; ADNI Investigators Plasma tau in Alzheimer disease. Neurology. 2016; 87(17): 1827- 1835. doi: 10.1212/WNL.0000000000003246 27694257 PMC5089525 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe present Elecsys assays produced among the best accuracies and are the first fully automated assays to have these greater accuracies.
“Although previous studies have found associations between CSF and PET Aβ and plasma Aβ using different immunoassays,7,12,13,14,44,45 the present Elecsys assays produced among the best accuracies and they are the first fully automated assays to have these greater accuracies.”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [7] Keshavan A, Heslegrave A, Zetterberg H, Schott JM Blood biomarkers for Alzheimer’s disease: much promise, cautious progress. Mol Diagn Ther. 2017; 21(1): 13- 22. doi: 10.1007/s40291-016-0241-0 27738910 source
Not checked in the free run.
- cites [12] Fandos N, Pérez-Grijalba V, Pesini P,; AIBL Research Group Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals. Alzheimers Dement (Amst). 2017; 8: 179- 187. 28948206 PMC5602863 source
Not checked in the free run.
- cites [13] Janelidze S, Stomrud E, Palmqvist S, Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci Rep. 2016; 6: 26801. doi: 10.1038/srep26801 27241045 PMC4886210 source
Not checked in the free run.
- cites [14] Lue LF, Sabbagh MN, Chiu MJ, Plasma levels of Aβ42 and tau identified probable Alzheimer’s dementia: findings in two cohorts. Front Aging Neurosci. 2017; 9: 226. doi: 10.3389/fnagi.2017.00226 28790911 PMC5522888 source
Not checked in the free run.
- cites [44] Kim HJ, Park KW, Kim TE, Elevation of the plasma Aβ40/Aβ42 ratio as a diagnostic marker of sporadic early-onset Alzheimer’s disease. J Alzheimers Dis. 2015; 48(4): 1043- 1050. doi: 10.3233/JAD-143018 26444752 source
Not checked in the free run.
- cites [45] Mayeux R, Honig LS, Tang MX, Plasma A[beta]40 and A[beta]42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology. 2003; 61(9): 1185- 1190. doi: 10.1212/01.WNL.0000091890.32140.8F 14610118 source
Not checked in the free run.
- Rests on an assumption: Mass spectrometry-based techniques are labor-intensive, time-consuming, low-throughput methods that currently are not feasible to implement in clinical practice on a large scale.
- Rests on an assumption: Fully automated Elecsys assays are already implemented in many clinical chemistry laboratories worldwide that provide analyses (eg, for primary care).
Classified as probably not a substantial claim. May combine two claims.
PremisecitationDetection of abnormal Aβ accumulation (Aβ positivity) may support the clinical diagnosis of AD and is essential for including participants in clinical AD trials targeting Aβ.
“Detection of abnormal Aβ accumulation (Aβ positivity) may support the clinical diagnosis of AD1,2 and is essential for including participants in clinical AD trials targeting Aβ.3”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Albert MS, DeKosky ST, Dickson D, The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 270- 279. doi: 10.1016/j.jalz.2011.03.008 21514249 PMC3312027 source
Not checked in the free run.
- cites [2] McKhann GM, Knopman DS, Chertkow H, The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011; 7(3): 263- 269. doi: 10.1016/j.jalz.2011.03.005 21514250 PMC3312024 source
Not checked in the free run.
- cites [3] Mattsson N, Carrillo MC, Dean RA, Revolutionizing Alzheimer’s disease and clinical trials through biomarkers. Alzheimers Dement (Amst). 2015; 1(4): 412- 419. 27239522 PMC4879481
Not checked in the free run.
May combine two claims.
PremisecitationMore recent studies have demonstrated that the plasma Aβ42/Aβ40 ratio correlates with brain Aβ and can differentiate patients with AD from healthy control participants.
“more recent studies have demonstrated that it correlates with brain Aβ and can differentiate patients with AD from healthy control participants.12,13”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [12] Fandos N, Pérez-Grijalba V, Pesini P,; AIBL Research Group Plasma amyloid β 42/40 ratios as biomarkers for amyloid β cerebral deposition in cognitively normal individuals. Alzheimers Dement (Amst). 2017; 8: 179- 187. 28948206 PMC5602863 source
Not checked in the free run.
- cites [13] Janelidze S, Stomrud E, Palmqvist S, Plasma β-amyloid in Alzheimer’s disease and vascular disease. Sci Rep. 2016; 6: 26801. doi: 10.1038/srep26801 27241045 PMC4886210 source
Not checked in the free run.
May combine two claims.
PremisecitationMeasuring plasma Aβ presents the same challenges as measuring CSF Aβ in that several analysis methods exist and unified cutoffs have been difficult to establish, even using the same assay, owing to high variability between laboratories and assay batches.
“Measuring plasma Aβ presents the same challenges as measuring CSF Aβ in that several analysis methods exist and unified cutoffs have been difficult to establish, even using the same assay, owing to high variability between laboratories and assay batches.21,22”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [21] Mattsson N, Andreasson U, Persson S,; Alzheimer’s Association QC Program Work Group CSF biomarker variability in the Alzheimer’s Association quality control program [published correction appears in Alzheimers Dement. 2015;11(2):237]. Alzheimers Dement. 2013; 9(3): 251- 261. doi: 10.1016/j.jalz.2013.01.010 23622690 PMC3707386
Not checked in the free run.
- cites [22] Vos SJ, Visser PJ, Verhey F, Variability of CSF Alzheimer’s disease biomarkers: implications for clinical practice. PLoS One. 2014; 9(6): e100784. doi: 10.1371/journal.pone.0100784 24959687 PMC4069102
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe significant findings were very similar when adjusting for age and sex.
“The significant findings were very similar when adjusting for age and sex (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductcitationAn unbiased cutoff of less than 0.059 was used to define Aβ positivity based on mixture modeling statistics, which previously has proved to provide robust and accurate thresholds.
“An unbiased cutoff of less than 0.059 was used to define Aβ positivity based on mixture modeling statistics, which previously has proved to provide robust and accurate thresholds.35,36”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [35] Bertens D, Tijms BM, Scheltens P, Teunissen CE, Visser PJ Unbiased estimates of cerebrospinal fluid β-amyloid 1-42 cutoffs in a large memory clinic population. Alzheimers Res Ther. 2017; 9(1): 8. doi: 10.1186/s13195-016-0233-7 28193256 PMC5307885 source
Not checked in the free run.
- cites [36] Palmqvist S, Schöll M, Strandberg O, Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat Commun. 2017; 8(1): 1214. doi: 10.1038/s41467-017-01150-x 29089479 PMC5663717 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitationβ-Amyloid can be detected in vivo using PET with ligands that bind to Aβ fibrils or by measuring levels of Aβ1-42 (Aβ42) in CSF.
“β-Amyloid can be detected in vivo using positron emission tomography (PET) with ligands that bind to Aβ fibrils or by measuring the levels of the peptide Aβ1-42 (Aβ42) in cerebrospinal fluid (CSF).4”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Blennow K, Mattsson N, Schöll M, Hansson O, Zetterberg H Amyloid biomarkers in Alzheimer’s disease. Trends Pharmacol Sci. 2015; 36(5): 297- 309. doi: 10.1016/j.tips.2015.03.002 25840462 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenPlasma NFH, NFL, and APOE genotype were not available in the validation cohort.
“Plasma NFH, NFL, and APOE genotype were not available in the validation cohort.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFor Elecsys immunoassays, CSF cutoffs established in one European cohort could be applied to another independent cohort in the United States to determine amyloid PET status with high accuracy.
“For example, for the Elecsys immunoassays (Roche Diagnostics), it has been shown that CSF cutoffs established in one European cohort could be applied to another independent cohort in the United States to determine amyloid PET status with high accuracy.24”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Hansson O, Seibyl J, Stomrud E,; Swedish BioFINDER study group; Alzheimer’s Disease Neuroimaging Initiative CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018; 14(11): 1470- 1481. doi: 10.1016/j.jalz.2018.01.010 29499171 PMC6119541 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe current standardized plasma handling protocol is consistent with recent findings that blood must be centrifuged within 1 hour and frozen shortly thereafter; up to 3 freeze-thaw cycles and 5 tube transfers do not affect plasma Aβ and tau values.
“The current standardized protocol is consistent with recent findings that blood must be centrifuged within 1 hour and frozen shortly thereafter; however, up to 3 freeze-thaw cycles and 5 tube transfers do not affect plasma Aβ and tau values.30”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Rózga M, Bittner T, Batrla R, Karl J Preanalytical sample handling recommendations for Alzheimer’s disease plasma biomarkers. Alzheimers Dement (Amst). 2019; 11: 291- 300.. 30984815 PMC6446057 source
Not checked in the free run.
May combine two claims.
Study design and conductown dataThe validation cohort had a smaller population size, resulting in a lack of analyses in subpopulations.
“Limitations of the present validation analysis include the lack of APOE data, the lack of improvement when replicating the model that included plasma tau, and the smaller population size, resulting in a lack of analyses in subpopulations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThis robust result is similar to what has been shown when using the Elecsys assays for CSF to establish a cutoff in one cohort and replicating it in a second cohort.
“This robust result is similar to what has been shown when using the Elecsys assays for CSF to establish a cutoff in one cohort and replicating it in a second cohort.24”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Hansson O, Seibyl J, Stomrud E,; Swedish BioFINDER study group; Alzheimer’s Disease Neuroimaging Initiative CSF biomarkers of Alzheimer’s disease concord with amyloid-β PET and predict clinical progression: A study of fully automated immunoassays in BioFINDER and ADNI cohorts. Alzheimers Dement. 2018; 14(11): 1470- 1481. doi: 10.1016/j.jalz.2018.01.010 29499171 PMC6119541 source
Not checked in the free run.
May combine two claims.
PremisecitationNFL is generally a late biomarker in the disease process and a non-AD specific biomarker for axonal degeneration.
“Because NFL generally is late biomarker in the disease process and a non–AD specific biomarker for axonal degeneration,15 the poor result could be because most of the participants (513 of 842) were cognitively unimpaired and only 64 had AD dementia.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Mattsson N, Andreasson U, Zetterberg H, Blennow K; Alzheimer’s Disease Neuroimaging Initiative Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol. 2017; 74(5): 557- 566. doi: 10.1001/jamaneurol.2016.6117 28346578 PMC5822204 source
Not checked in the free run.
The paper relies on this without support.
The costs and limited access to PET or CSF analysis restrict their use to a minority of cases.
“The costs and limited access to PET or CSF analysis may restrict their use to a minority of cases.”
The paper relies on this without support.
There is a great need for readily available methods that can detect brain Aβ.
“There is thus a great need for readily available methods that can detect brain Aβ, and perhaps the most desirable goal has been to establish blood-based biomarkers of Aβ.”
The paper relies on this without support.
Prior promising plasma Aβ studies are costly and need extensive development before they can be implemented in primary care or large screenings.
“Although these studies are promising and show the potential of plasma Aβ as a true AD biomarker, they are costly and need extensive development before they can be implemented in primary care or in large screenings where cost-effective, fully automated, high-throughput, and highly reliable analysis methods are needed.”
The paper relies on this without support.
Mass spectrometry-based techniques are labor-intensive, time-consuming, low-throughput methods that currently are not feasible to implement in clinical practice on a large scale.
“However, these are labor-intensive, time-consuming, low-throughput methods that currently are not feasible to implement in clinical practice on a large scale.”
The paper relies on this without support.
Fully automated Elecsys assays are already implemented in many clinical chemistry laboratories worldwide that provide analyses (eg, for primary care).
“Fully automated Elecsys assays, on the other hand, are already implemented in many clinical chemistry laboratories worldwide that provide analyses (eg, for primary care).”
The paper relies on this without support.
There is an ongoing great need to recruit large cohorts for AD drug trials in preclinical and prodromal stages.
“Although further validation studies are needed, this illustrates the potential usefulness blood assays might have, especially considering the ongoing great need to recruit large cohorts for AD drug trials in preclinical and prodromal stages.”
The paper relies on this without support.
Aβ40 acts as a reference peptide that accounts for interindividual variability in the overall Aβ production and CSF turnover.
“Here, Aβ40 acts as a reference peptide that accounts for interindividual variability in the overall Aβ production and CSF turnover.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CNS Aβ deposition can be detected via plasma assessment of Aβ species.
“Recent studies demonstrate the ability to detect CNS Aβ deposition via the use of plasma assessment of Aβ species”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Palmqvist et al., 2019
Plasma Aβ acts as an endophenotype of AD, simultaneously changing with Aβ status in the brain.
“there is increasing evidence to support that plasma Aβ acts as an endophenotype of AD, which simultaneously changes with Aβ status in the brain.”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [272]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Aβ-positive cutoff includes equality in one place but excludes it in another
MinorThe methods define positivity as a CSF ratio strictly less than 0.059, while the figure caption defines it as less than or equal to 0.059. A participant with a ratio exactly equal to 0.059 would be classified differently.
“An unbiased cutoff of less than 0.059 was used to define Aβ positivity”
“Aβ-positive (Aβ+) (CSF Aβ42/Aβ40 ≤ 0.059) and Aβ-negative (Aβ−) (CSF Aβ42/Aβ40 > 0.059) groups.”
Reported CSF ratio SD is incompatible with the group cutoff
MinorTable 1 reports an SD of 0.098 for the MCI Aβ-positive CSF ratio. Because this group's ratios are nonnegative and at most 0.059, an SD that large is impossible with the reported mean of 0.040.
“| Aβ42/Aβ40 | 0.091 (0.016) | 0.042 (0.009)b | 0.090 (0.014) | 0.040 (0.098)b | 0.037 (0.009)b |”
“β-Amyloid status was defined based on a CSF Aβ42/Aβ40 cutoff of ≤0.059. Data are shown as mean (SD) unless otherwise specified.”
Aβ40 group comparison cites the ratio panel
MinorThe text cites Figure 1E for the stratified plasma Aβ40 comparison, whereas the figure caption assigns Aβ40 to panel D and the ratio to panel E for the unstratified comparison.
“Plasma Aβ40 levels were lower in the AD Aβ-positive dementia group compared with all other groups (P < .001 for all), but there were no differences between CU Aβ-negative, CU Aβ-positive, and MCI Aβ-positive participants (Figure 1E).”
“Plasma Aβ42 (A), Aβ40 (C), and the plasma Aβ42/Aβ40 ratio (E) in the Aβ-positive (Aβ+) (CSF Aβ42/Aβ40 ≤ 0.059) and Aβ-negative (Aβ−) (CSF Aβ42/Aβ40 > 0.059) groups.”
Aβ42 group comparison cites the Aβ40 panel
MinorThe text directs readers to Figure 1D for the stratified plasma Aβ42 comparison, but the figure caption identifies panel B as Aβ42 and panel D as Aβ40.
“The decrease in plasma Aβ42 was more pronounced in AD Aβ-positive dementia compared with CU Aβ-positive and MCI Aβ positive groups.”
“Plasma Aβ42 (B), Aβ40 (D), and the plasma Aβ42/Aβ40 ratio (F) in the CU, MCI, and AD participant groups stratified by Aβ status.”
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Self-citationPlasma neurofilament light chain levels in Alzheimer’s disease
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Self-citationPlasma Tau Association with Brain Atrophy in Mild Cognitive Impairment and Alzheimer’s Disease
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Self-citationIncreased amyloidogenic APP processing in APOE ɛ4-negative individuals with cerebral β-amyloidosis
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Self-citationBlood Protein Markers of Neocortical Amyloid-β Burden: A Candidate Study Using SOMAscan Technology
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Blood Biomarkers for Alzheimer’s Disease: Much Promise, Cautious Progress
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Self-citation
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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
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Self-citationJanelidze, S., Mattsson, N., Palmqvist, S., Smith, R., Beach, T. G., Serrano, G. E., Chai, X., Proctor, N. K., Eichenlaub, U., Zetterberg, H., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0755-1 · Cited by 1,247 · see citing works
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Self-citationAmyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
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Self-citationPlasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease
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Atypical Alzheimer Disease Variants
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- Authors
- Palmqvist, S., Janelidze, S., Stomrud, E., Zetterberg, H., Karl, J., Zink, K., Bittner, T., Mattsson, N., Eichenlaub, U., Blennow, K., & Hansson, O.
- Affiliations
- Lund University (SE)
- Sahlgrenska University Hospital (SE)
- Roche Diagnostics GmbH, Penzberg, Germany
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Palmqvist, Sebastian
- Hansson, Oskar
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-09-01
- Volume
- 76
- Issue
- 9
- Pages
- 1060
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC6593637
- OpenAlex
- W2952677120
- Semantic Scholar
- a2f86baa48f311363b835c73926531f63b542e6b
- Cited by
- 435
- References
- 41
- Citations by year
- 2026: 38 · 2025: 48 · 2024: 79 · 2023: 65 · 2022: 63 · 2021: 75 · 2020: 51 · 2019: 15 · 2015: 1
- FWCI
- 40.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Neurology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Clinical Laboratory Practices and Quality Control
- Keywords
- Alzheimer's disease, plasma amyloid-beta, plasma tau, blood-based biomarkers, automated immunoassay, APOE genotype, neurofilament light chain, neurofilament heavy chain, mild cognitive impairment, diagnostic accuracy
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