Abstract
To facilitate clinical trials of disease-modifying therapies for Alzheimer’s disease, which are expected to be most efficacious at the earliest and mildest stages of the disease1,2, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain—the earliest pathological signature of Alzheimer’s disease—are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable3,4. Despite much effort3,4,5,6,7, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669–711/amyloid-β (Aβ)1–42 and Aβ1–40/Aβ1–42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer’s disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1–42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost–benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.
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Acknowledgements
The NCGG study group thank all participants of the study, clinicians who referred patients, and all the staff who supported the MULNIAD project. We thank N. Sugimoto for conducting statistical analyses, S. Niida and the NCGG Biobank members for the management of plasma samples and M. Kawakage for data monitoring. This study was supported by The Research Funding for Longevity Sciences (25-24 and 26-30) from the National Center for Geriatrics and Gerontology, and partially supported by Research and Development Grants for Dementia from the Japan Agency for Medical Research and Development, AMED. This study is registered under UMIN ID: 000016144. The AIBL study would like to thank all participants of the study and the clinicians who referred participants. The AIBL study (https://aibl.csiro.au/) is a consortium between Austin Health, CSIRO, Edith Cowan University and the Florey Institute, The University of Melbourne. Partial financial support was provided by the Alzheimer’s Association (US), the Alzheimer’s Drug Discovery Foundation, an anonymous foundation, the Cooperative Research Centre for Mental Health, CSIRO Science and Industry Endowment Fund, the Dementia Collaborative Research Centres, the Victorian Government Operational Infrastructure Support program, the McCusker Alzheimer’s Research Foundation, the National Health and Medical Research Council, and the Yulgilbar Foundation. Funding sources had no role in study design, data collection, data analyses or data interpretation.
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Contributions
A.N., N.K., T.K., K.It., K.T., and K.Y. designed the study. A.N., N.K., V.L.V., C.L.M., and K.Y. wrote the manuscript and A.N., N.K., V.L.V., V.D., T.T., and K.M. made the figures. A.N., V.L.V., T.K., V.D., C.F., Q.-X.L., R.M., C.R., Ke.Is., Ka.Is., Y.A., and C.L.M. collected the data. A.N., N.K., V.L.V., T.K., J.D., V.D., C.F., Q.-X.K., R.M., C.R., Y.A., T.T., K.M., S.I., K.It., K.T., and C.L.M. analysed the data. All authors interpreted the data and critically revised the manuscript.
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N.K., S.I. and K.T. are employees of Shimadzu. NCGG and Shimadzu have patents pending that are related to this study: PCT/JP2016/076706 and PCT/JP2015/064386. Shimadzu has patents pending: JP 2015-140899 and US 15/209331. V.L.V. received grants from CSIRO and NHMRC during the study. J.D. received grants from CRC for Mental Health, during the study, and has patent TW8546/AU pending.
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Reviewer Information Nature thanks H. Federoff, R. Thomas and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Extended data figures and tables
Extended Data Figure 1 The amino acid sequences of Aβ-related peptides and results of the pilot study.
a, Overview of the amino acid sequences of the Aβ-related peptides Aβ1–40, Aβ1–42 and APP669–711. b, ROC analyses of the blinded pilot study for 20 Aβ+ and 20 Aβ− subjects (see Supplementary Information). The green, blue, and red curves indicate APP669–711/Aβ1–42, Aβ1–40/Aβ1–42 and the composite biomarker, respectively. The AUCs and the representative best values of sensitivity, specificity and accuracy for these biomarkers as determined by Youden’s index are as follows: APP669–711/Aβ1–42, AUC = 0.923, sensitivity = 0.850, specificity = 0.950, accuracy = 0.900; Aβ1–40/Aβ1–42, AUC = 0.930, sensitivity = 0.900, specificity = 0.900, accuracy = 0.900; composite biomarker, AUC = 0.975, sensitivity = 0.950, specificity = 0.950, accuracy = 0.950.
Extended Data Figure 2 Peptide and biomarker values, and their distributions.
a, The Aβ-related peptide and biomarker values in each study site (NCGG and AIBL). Normalized intensity of each peptide (top), and values for each biomarker (bottom) in the NCGG (n = 121) and AIBL overall (n = 252) data sets. Composite biomarker values are the average of the normalized values of APP669–711/Aβ1–42 and Aβ1–40/Aβ1–42. Peptide values are arbitrary units. Means and 95% confidence intervals (CI) in parentheses; P values show statistical differences between the Aβ+ and Aβ− groups (two-sided Student’s t-test or Welch’s t-test). Superscripts indicate statistically significant site differences (aP = 0.012, bP = 0.002, cP = <0.0001, two-sided). These site differences did not change when using analysis of covariance (ANCOVA) adjusted for semi-quantitative measures of Aβ-PET, using SUVR (PIB) and BeCKeT (FLUTE and FBP) values. b, Histograms of the biomarker value distributions for APP669–711/Aβ1–42, Aβ1–40/Aβ1–42 (top), and their inversions (Aβ1–42/APP669–711 and Aβ1–42/Aβ1–40) (bottom). Blue and red bars represent the distributions of Aβ− and Aβ+ populations, respectively. P values represent the results of the Shapiro–Wilk test (see Methods).
Extended Data Figure 3 Adjusted ROC analyses corresponding to Fig. 2.
a, ROC analyses for each biomarker when predicting individual Aβ+/Aβ− status for the discovery, validation, and combined data sets. Adjusted (age, gender, APOE4, and clinical category) analyses for the NCGG PIB discovery data (left), AIBL PIB validation data (middle), and AIBL overall (all tracers) validation data (right). See Extended Data Table 1a for detailed performance values. Data are from 121, 111 and 252 individuals for the NCGG PIB, AIBL PIB and AIBL overall data, respectively. b, Comparisons of biomarker performances within each analysis corresponding to the ROC curves in a. Each colour bar represents the AUC and 95% confidence interval. Statistically significant differences between two AUCs (DeLong test) and significant increments in predictive ability as assessed by NRI and IDI are indicated as in Fig. 2. All P values are two-sided, and Bonferroni corrected (multiplied by the number of comparisons, 6). Note that the NRI in the comparison between Aβ1–40/Aβ1–42 and the composite biomarker in NCGG data was negative (NRI = −0.382) indicating that the reclassification ability is lower in the composite biomarker. c, Adjusted (age, gender, APOE4 and clinical category) ROC analyses of the composite biomarker compared by different PET tracers; PIB (NCGG, n = 121, and AIBL, n = 111), flutemetamol (AIBL, n = 81), and florbetapir (AIBL, n = 60). See Extended Data Table 1b for detailed performance values. d, e, Adjusted (age, gender, APOE4) ROC curves of the composite biomarker within the AD and MCI (d) and cognitively normal (e) groups. Sample sizes are the same as those listed in Fig. 2d, e; see Extended Data Table 1c for detailed performance values.
Extended Data Figure 4 Correlations between plasma biomarkers and brain Aβ burden: additional data related to Fig. 3a.
a–c, Biomarker values plotted against SUVR values from PIB-PET imaging; Aβ1-42 (a), APP669-711/Aβ1-42 (b) and Aβ1–42/Aβ1–40 (c). Data are from 121 (NCGG PIB, top) and 111 (AIBL PIB, bottom) individuals. Colours represent the clinical categories: AD, red; MCI, orange; cognitively normal, blue. The vertical dashed lines represent cut-off values of PIB-PET imaging (1.4), and horizontal dashed lines represent the common cut-off values of the plasma biomarkers estimated in Extended Data Fig. 7. d, A summary table for the correlation analyses. The sample sizes for each data set are; NCGG PIB, n = 121; AIBL PIB, n = 111; NCGG + AIBL PIB, n = 232; AIBL FLUTE, n = 81; AIBL FBP, n = 60; and NCGG + AIBL overall, n = 373. Pearson’s correlation coefficients (r) and their significance (two-sided P) are presented in the plots and the table.
Extended Data Figure 5 Reliability of the IP–MS methods.
a, Standard curves of Aβ1–42 (left), Aβ1–40 (middle), and APP669–711 (right) in PBS containing BSA. The standard curves were generated over a 2.5–40 pM range for Aβ1–42 and APP669–711, and a 10–160 pM range for Aβ1–40. The linearity was evaluated with the coefficient of determination (R2). The error bars indicate the standard deviations of normalized intensities obtained from four mass spectra. The normalized intensities (AU) and signal-to-noise ratios at the lowest concentration were 0.119 AU and 10.9 for Aβ1–42, 0.152 AU and 16.1 for APP669–711 and 1.56 AU and 165 for Aβ1-40, respectively. The lower limit of quantification referred to the lowest concentration at which Aβ1–42, APP669–711 and Aβ1–40 showed a signal-to-noise ratio greater than 10. Data reproducibility was confirmed by two additional experiments. b, Relationships between plasma dilution and normalized intensity of endogenous Aβ1–42, Aβ1–40, and APP669–711, which were contained in the human plasma. Normalized intensity indicates the mass spectrometry signal normalized with the signal for SIL-Aβ1–38. The linearity was evaluated with R2. The error bars indicate the standard deviations of normalized intensities obtained from four mass spectra. The data reproducibility was confirmed by one additional experiment. c, Signal linearity of plasma peptides spiked with synthetic Aβ1–42, synthetic Aβ1–40, and synthetic APP669–711. The plasma samples, which were spiked over a 2.5–40 pM range for Aβ1–42 and APP669–711, and a 10–160 pM range for Aβ1–40, were prepared and measured by the IP–MS method. The linearity was evaluated with R2. The error bars indicate the standard deviations of normalized intensities obtained from four mass spectra. The data reproducibility was confirmed by one additional experiment. d, Normalized signal intensity of Aβ1–42, Aβ1–40, and Aβ1–40/Aβ1–42 in 19 subjects measured by two methods; using common internal standard SIL-Aβ1–38 (x axis) and using corresponding SIL-peptides (y axis). Pearson’s correlation coefficients (r) and their significance (two-sided P) are presented in the plots. The experiments were performed once. e, ROC analyses for Aβ1–42 and Aβ1–40/Aβ1–42 to distinguish between Aβ+ and Aβ− individuals (n = 19) of the two methods; using the common internal standard SIL-Aβ1–38 (left) and using the corresponding SIL-peptides (right). f, Tables showing the performance values corresponding to e, as determined by ROC analyses and Youden’s index.
Extended Data Figure 6 Cellular and molecular characteristics of APP669–711.
a, Results of additional experiment 1 (Supplementary Information). Aβ-related peptides produced from human neuroblastoma cell line. MALDI–TOF mass spectra of Aβ-related peptides in human plasma (top), BE(2)-C cell culture supernatant (middle) and medium without cell culture (bottom). Representative spectra from five experiments are shown. The theoretical m/z values of peptides are 4,330.9 for Aß1–40, 4,515.1 for Aß1–42, and 4,689.4 for APP669–711. SIL-Aβ1–38 was used as an internal standard for the normalization of mass spectra. b–d, Results of additional experiment 2 (Supplementary Information). b, Kinetics of fibril formation. Aβ1-42 (15 μM, open circles) or APP669–711 (15 μM, closed circles) were incubated in PBS at 37 °C. Fibril formation was monitored using the thioflavin T spectroscopic assay. Data are mean ± s.d. from four (Aβ1–42) or five (APP669–711) experiments. c, Size exclusion chromatography. Aβ1–42 (15 μM, left) or APP669–711 (15 μM, right) were incubated in PBS at 37 °C, and the supernatants were centrifuged (10,000g for 10 min) and subjected to size-exclusion chromatography (Sephacryl S-300 HR) at 0 (black), 3 (red), 6 (blue), 12 (orange), and 24 h (green). The elution times for molecular mass standards (kDa) are indicated by arrows. d, Changes in secondary structure during peptide aggregation. Aβ1–42 (15 μM, left) and APP669–711 (15 μM, right) were incubated in PBS at 37 °C, and circular dichroism spectra were measured at 0 (black), 3 (red), 6 (blue), 12 (orange), and 24 h (green). Experiments in b–d were each performed once.
Extended Data Figure 7 Common cut-off values are applicable for both NCGG and AIBL data sets.
a, Unadjusted ROC analyses for each biomarker when predicting individual Aβ+/Aβ− status for the NCGG + AIBL PIB (left, n = 232) and NCGG + AIBL overall (right, n = 373) data sets. b, Comparisons of biomarker performances within each analysis corresponding to the ROC curves in a. Each colour bar represents the AUC and 95% confidence. Statistically significant differences between two AUCs (DeLong test) and significant increments in predictive ability as assessed by NRI and IDI are indicated as in Fig. 2. All P values are two-sided, and Bonferroni corrected (multiplied by the number of comparisons, 6). c, Biomarker performances when applying the same cut-off values to each data set. For each biomarker, an optimal common cut-off value was determined by the Youden’s index of the ROC analysis for the NCGG + AIBL overall data set. The sensitivity, specificity and accuracy were then calculated at the common cut-off point for each biomarker in all data sets. d, Diagnostic performance plots for Aβ1–42, APP669–711/Aβ1–42, Aβ1–40/Aβ1–42 and the composite biomarker. Each row from top to bottom shows the plots for the NCGG PIB, AIBL PIB, AIBL overall, NCGG + AIBL PIB, and NCGG + AIBL overall data (unadjusted), respectively. Sensitivity (orange), specificity (blue) and accuracy (green) were plotted using the values of the biomarkers (x axis). The vertical dashed lines indicate the common cut-off values as shown in c. The blue and pink shaded squares indicate ranges in which a biomarker can perform with at least 80% and 85% accuracy, respectively.
Extended Data Figure 8 Possible clinical utility of the plasma biomarker.
a, b, Diagnostic performance plots for the composite biomarker in two specific settings (see Supplementary Discussion). a, Diagnostic performance plots for subjects with MCI in the AIBL PIB unadjusted data (n = 33) (left). The prevalence of Aβ-positivity for subjects with MCI was assumed to be 66%. Sensitivity (orange), specificity (blue), accuracy (green), PPV (red, dashed) and NPV (dark blue, dashed) were plotted against the values of the composite biomarker (x axis). The black vertical dashed line indicates a cut-off point as determined by the Youden’s index (y point) in the AIBL PIB data. At the y point, the sensitivity and specificity were 0.900 and 0.923, respectively. With these values, relationships between the prevalence and PPV or NPV were plotted (right). Note that these data do not correspond to the ROC analysis shown in Fig. 2d, because this diagnostic performance plot analysis does not contain subjects with AD. b, Diagnostic performance plots for cognitively normal subjects in the AIBL PIB unadjusted data (n = 63) (left). The prevalence of Aβ-positivity in general elderly people was assumed to be 30%. At the y point, the sensitivity and specificity were 0.880 and 0.868, respectively. With these values, relationships between the prevalence and PPV or NPV were also plotted (right). c–g, Results of the additional analysis for subjects with and without AD (see Supplementary Discussion). c, Sample numbers for subjects with and without AD. d, Detailed clinical diagnoses of subjects without AD. e, ROC analyses for each plasma biomarker in the overall data (n = 51). f, ROC analysis of the composite biomarker in the overall (n = 51), AD (n = 31), and non-AD (n = 20) groups. g, Performance of the composite biomarker using the common cut-off value. The AUC values were computed from the ROC analysis and sensitivity, specificity, and accuracy were computed by applying the common cut-off value for the composite biomarker (0.376).
Extended Data Figure 9 Optimal generation of the composite biomarker.
Unadjusted ROC analyses of the composite biomarkers generated by different weightings (see Supplementary Discussion). a, Comparisons of the composite biomarkers generated by different weights for APP669–711/Aβ1–42 and Aβ1–40/Aβ1–42 normalized values (z-scores) in the discovery NCGG PIB data (n = 121, left) and validation AIBL PIB data (n = 111, right). The composite biomarker generated by the original weight (1:1) is coloured red, the weight estimated by the NCGG data (1.14:3.59) green, and the weight estimated by the AIBL data (3.04:1.95) blue. b, A comparison of the composite biomarkers generated by using different reference databases. The original composite biomarker (normalized by NCGG data) is coloured red, and the alternative composite biomarker normalized by AIBL data is orange. c, Summary of the ROC analyses. The AUCs and the representative best values of sensitivity, specificity and accuracy for these biomarkers as determined by the Youden’s index are shown.
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Nakamura, A., Kaneko, N., Villemagne, V. et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 554, 249–254 (2018). https://doi.org/10.1038/nature25456
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DOI: https://doi.org/10.1038/nature25456
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