Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, Fowler C, Li QX, Martins R, Rowe C, Tomita T, Matsuzaki K, Ishii K, Ishii K, Arahata Y, Iwamoto S, Ito K, Tanaka K, Masters CL, Yanagisawa K. High performance plasma amyloid-β biomarkers for Alzheimer's disease. Nature. 2018 Feb 8;554(7691):249-254. Epub 2018 Jan 31 PubMed.

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  1. This is a great paper! For many years, it was hard to get a reliable amyloid biomarker signal from blood and many inconsistent results were published. Many researchers, including us, believed that peripheral production of Aβ (from platelets, hepatocytes, and other cell types) made Aβ a poor biomarker for cerebral beta-amyloidosis when measured in blood. It was also hard to quantify Aβ in blood because of its low concentration and stickiness to other blood proteins. Nevertheless, during recent years, a number of studies have shown that plasma Aβ concentrations can be reliably quantified and actually do reflect amyloid deposition in the brain, if the methods are sensitive and specific enough. These include Janelizde et al., 2016, who quantified plasma Aβ using an ultrasensitive single molecule array (SIMOA) method, and Kaneko et al., Panee et al., and Ovod et al., who used mass spectrometry (Janelizde et al., 2016; Kaneko et al., 2014; Pannee et al., 2014; Ovod et al., 2017). Now, this beautiful paper further corroborates this and shows even stronger associations, most likely because of further refinements of the method.

    References:

    Janelidze S, Stomrud E, Palmqvist S, Zetterberg H, van Westen D, Jeromin A, Song L, Hanlon D, Tan Hehir CA, Baker D, Blennow K, Hansson O. Plasma β-amyloid in Alzheimer's disease and vascular disease. Sci Rep. 2016 May 31;6:26801. PubMed.

    Kaneko N, Yamamoto R, Sato TA, Tanaka K. Identification and quantification of amyloid beta-related peptides in human plasma using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc Jpn Acad Ser B Phys Biol Sci. 2014;90(3):104-17. PubMed.

    Pannee J, Törnqvist U, Westerlund A, Ingelsson M, Lannfelt L, Brinkmalm G, Persson R, Gobom J, Svensson J, Johansson P, Zetterberg H, Blennow K, Portelius E. The amyloid-β degradation pattern in plasma--a possible tool for clinical trials in Alzheimer's disease. Neurosci Lett. 2014 Jun 24;573:7-12. Epub 2014 May 4 PubMed.

    Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, Hicks T, Schneider T, Sullivan M, Paumier K, Holtzman DM, Morris JC, Benzinger T, Fagan AM, Patterson BW, Bateman RJ. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017 Aug;13(8):841-849. Epub 2017 Jul 19 PubMed.

    View all comments by Henrik Zetterberg

  2. The authors should be congratulated on developing a highly specific blood test for amyloidosis and demonstrating it so well. It was a fantastic paper that found nearly identical results in performance of a mass spectrometry-based blood test for amyloid plaques to us (Ovod et al., 2017), and matches with our findings presented at AAIC that these results are highly reproducible across studies. The authors have done a top-notch job and the extensive studies across several cohorts confirming the findings and their work are impressive. The fact that two labs have independently accomplished this level of accuracy provides very high confidence this will be a robust way forward.

    References:

    Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, Hicks T, Schneider T, Sullivan M, Paumier K, Holtzman DM, Morris JC, Benzinger T, Fagan AM, Patterson BW, Bateman RJ. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017 Aug;13(8):841-849. Epub 2017 Jul 19 PubMed.

    View all comments by Randall Bateman

  3. It has long since been believed that measures of cerebrospinal fluid Aβ concentrations more likely reflect Aβ metabolism in the central nervous system (CNS). Previous studies on plasma Aβ have been contradictory and most groups have reported no change in plasma Aβ42 concentrations between Alzheimer´s disease patients and controls. In 2014 we published a paper in which we developed an immunoprecipitation method that we combined with mass spectrometric analysis to quantify several Aβ peptides in plasma (Pannee et al., 2014). In a small sample set including nine AD patients and 10 controls we were not able to detect a significant difference between the groups, but there was a trend toward lower concentrations of Aβ1-42 in AD.

    In this paper by Nakamura and colleagues, the authors have developed and optimized a highly sensitive method for relative quantification of three Aβ peptides: Aβ1-42, Aβ1-40, and APP669–711. The method is based on selective enrichment of the Aβ peptides by immunoprecipitation and analysis by MALDI TOF. For normalization of the data they used a stable-isotope-labeled Aβ1-38. The method was applied on two independent sample sets—one discovery data set comprising 121 subjects and one validation set including 252 subjects of which 111 individuals were diagnosed using amyloid positron-emission tomography (PET). The authors show convincingly that the plasma Aβ40/Aβ42 ratio indeed reflects CNS-derived Aβ since the plasma Aβ levels correlated with both CSF Aβ concentrations and amyloid PET. However, as the authors point out, the findings need to be replicated. More importantly, studies comparing available methods (mass spectrometry-based and immuno-based, such as ELISA) should be conducted in order to fully understand this novel promising plasma biomarker.

    References:

    Pannee J, Törnqvist U, Westerlund A, Ingelsson M, Lannfelt L, Brinkmalm G, Persson R, Gobom J, Svensson J, Johansson P, Zetterberg H, Blennow K, Portelius E. The amyloid-β degradation pattern in plasma--a possible tool for clinical trials in Alzheimer's disease. Neurosci Lett. 2014 Jun 24;573:7-12. Epub 2014 May 4 PubMed.

    View all comments by Erik Portelius

  4. As the authors state carefully and clearly, these findings need to be replicated, the analytic methods need to be confirmed, ROC performance in other brain diseases is needed, and validation in clinical trials of AB lowering agents is needed.

    That said, if we had an inexpensive, minimally invasive, and repeatable biomarker of cerebral amyloidosis, it would represent a major contribution to the field. This would allow acquisition of multiple measures in trials, for example, during a run-in period as well as during the treatment period. The gain in statistical power would be tremendous and would facilitate rapid go-no/go decisions inexpensively and allow us to address many more trial hypotheses quickly (e.g., dosing, combination therapy).

    View all comments by Pierre Tariot

  5. These results are very promising, and lend further support to the use of blood Aβ as a screening biomarker for brain amyloidosis. The results add to the recent paper published last year that also used immunoprecipitation and mass spectrometry for measurements (Ovod et al., 2017) and showed high concordance for the plasma Aβ42/Aβ40 ratio with amyloid PET, and outperform concordance obtained using immunoassay techniques such as SIMOA (Janelidze et al., 2016). For future possible clinical applications, it would be highly interesting to see a direct method comparison of the mass spectrometry and immunoassay techniques for quantification of blood Aβ.

    References:

    Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, Hicks T, Schneider T, Sullivan M, Paumier K, Holtzman DM, Morris JC, Benzinger T, Fagan AM, Patterson BW, Bateman RJ. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017 Aug;13(8):841-849. Epub 2017 Jul 19 PubMed.

    Janelidze S, Stomrud E, Palmqvist S, Zetterberg H, van Westen D, Jeromin A, Song L, Hanlon D, Tan Hehir CA, Baker D, Blennow K, Hansson O. Plasma β-amyloid in Alzheimer's disease and vascular disease. Sci Rep. 2016 May 31;6:26801. PubMed.

    View all comments by Kaj Blennow

  6. This is very interesting and promising discovery work. The authors provided an initial replication study in AIBL, which further supports this very early work. Much remains to be done, but I am excited by these findings and leveraging both of these studies was an excellent way to do the work. I really do applaud the authors for this effort. This is one of the largest such studies to date; however, the sample size is still relatively small so replication across additional studies and laboratories is still needed.

    The composite ratio score that is created from normalized intensities with Ab42 utilized twice in the formula is an interesting approach that could have skewed the data, given that this is the marker that was most impactful in the first place and the only one that was normally distributed. When you look at the bar graphs, there is tremendous overlap across groups. While the statistical approach is not what I would have anticipated, if others can replicate the use of this approach using these analytic methods, it is possible that the authors are onto something very novel and highly important. I would assume that others will be seeking access to the data set for independent analyses very soon to see if they can replicate the findings with different analytics.

    The real validation of any work in this area is prospective application within a primary care setting where such a biomarker is most needed: that is, a blood test to tell the primary care doctor if this specific patient should or should not be referred for confirmatory PET scans or LP for amyloid assay. The base rates and statistics will work out very differently than within a clinic-based cohort where 50 percent of those in the sample are amyloid-positive; in a primary care setting the majority of patients will not be amyloid-positive so you are looking for a minority of patients and need to cost-contain by screening out as many patients as possible (not to mention providing patients with a sense of ease with a negative finding). To date, no such study has been completed globally on any of the promising biomarkers, but this looks promising for such a setting.

    Overall, I am very encouraged by these findings. They are great for the field, as this particular line of work is very important and needed. It is still early discovery work and requires additional validation, but I am cautiously optimistic.

    View all comments by Sid O'Bryant

  7. This is a well-planned, impressive study that relates brain Aβ amyloidosis with plasma Abeta and related peptide parameters. The methods used, IP-MS, are relatively simple, so there are going to be additional studies that try to confirm the observations made here.

    It was a smart idea to use isotope Aβ1-38 as an internal control, although it remains unclear to me why the authors avoided using the Aβ1-42/Aβ1-38 ratio for the prediction.

    The other question is "Where do all the Aβ and related peptides come from?" If they are derived from vascular endothelial cells and platelets, then the cause-and-effect relationship and mechanism become unclear.

    References:

    Kitazume S, Tachida Y, Kato M, Yamaguchi Y, Honda T, Hashimoto Y, Wada Y, Saito T, Iwata N, Saido T, Taniguchi N. Brain endothelial cells produce amyloid {beta} from amyloid precursor protein 770 and preferentially secrete the O-glycosylated form. J Biol Chem. 2010 Dec 17;285(51):40097-103. PubMed.

    View all comments by Takaomi Saido

  8. This plasma assay used IP-MS methodology, with standardization of plasma levels of Aβ42, 40, and a novel peptide by inclusion of Aβ38. The assay methods are well described, and the CV’s for the various plasma measures were low (around 5 percent). There was high sensitivity and specificity when calibrated against amyloid PET imaging and (in a much smaller subset of subjects) against CSF Aβ42 measured by ELISA. The findings represent a step forward in developing a plasma screening test for CNS amyloid deposition, and the study design, with discovery and replication cohorts, is commendable.

    Several recent studies on plasma Aβ are not mentioned in this manuscript. In particular, Ovod et al. used a similar IP-MS approach with internal standards to quantify plasma Aβ42 and 40, and found comparably strong relationships with markers of CNS amyloid, albeit in a single Center study (Ovod et al., 2017). Another study measured soluble and bound forms of Aβ in plasma in the AIBL cohort, and found estimates of sensitivity and specificity in that cohort that appear similar to those for AIBL in the present study (Fandos et al., 2017). The differences between the extremely high sensitivity/specificity in the Japanese cohort and the lower sensitivity and specificity (and overlap in values presented in Figure 1 for AIBL) is not well explained. As a general comment, for many biomarkers, initial performance through best fits to develop cutoffs in discovery cohorts is often higher than performance in follow-up studies.

    Given the expense of amyloid PET imaging, the use of a plasma marker to improve the efficiency of ordering a confirmatory test is supported by this study, and replication, extension, and comparison with other methods will take us much closer to this goal.

    References:

    Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, Hicks T, Schneider T, Sullivan M, Paumier K, Holtzman DM, Morris JC, Benzinger T, Fagan AM, Patterson BW, Bateman RJ. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017 Aug;13(8):841-849. Epub 2017 Jul 19 PubMed.

    Fandos N, Pérez-Grijalba V, Pesini P, Olmos S, Bossa M, Villemagne VL, Doecke J, Fowler C, Masters CL, Sarasa M, 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. Epub 2017 Sep 12 PubMed.

    View all comments by Douglas Galasko

  9. This is an important paper and a significant advance in the field. The key question remaining concerns the relevance of Aβ40 and/or 42 in the etiology of the disease and whether this reflects a downstream event in the pathological process. 

    View all comments by Frédéric Checler

  10. The article by Nakamura et al. is really good news for those who have been working on developing Aβ blood-based biomarkers for a long time. 

    The feeling in this particular research area, traditionally overwhelmed by controversy, started to change when the validation gold standard was changed from the clinical diagnosis to Aβ burden in the brain (as determined by PET or CSF analysis).

    New approaches are always welcome and Nakamura’s paper, together with the previous by Ovod et al. and by Janelidze et al., have dramatically helped elucidate that inexpensive blood-based biomarkers are viable and should be a top research priority for advancement in the fight against AD. In our own studies (Fandos et al., 2017), we have shown that validated ELISA tests for plasma Aβ (Pérez-Grijalba et al., 2016), at reference laboratories, can also be developed into a useful prescreening tool for secondary prevention clinical trials.

    However, we should be aware that an early and accurate diagnosis of such a complex disease as AD will most likely require a combination of biomarkers that reflect the different pathological mechanisms driving the disease progression.

    References:

    Fandos N, Pérez-Grijalba V, Pesini P, Olmos S, Bossa M, Villemagne VL, Doecke J, Fowler C, Masters CL, Sarasa M, 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. Epub 2017 Sep 12 PubMed.

    Janelidze S, Stomrud E, Palmqvist S, Zetterberg H, van Westen D, Jeromin A, Song L, Hanlon D, Tan Hehir CA, Baker D, Blennow K, Hansson O. Plasma β-amyloid in Alzheimer's disease and vascular disease. Sci Rep. 2016 May 31;6:26801. PubMed.

    Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, Hicks T, Schneider T, Sullivan M, Paumier K, Holtzman DM, Morris JC, Benzinger T, Fagan AM, Patterson BW, Bateman RJ. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement. 2017 Aug;13(8):841-849. Epub 2017 Jul 19 PubMed.

    Pérez-Grijalba V, Fandos N, Canudas J, Insua D, Casabona D, Lacosta AM, Montañés M, Pesini P, Sarasa M. Validation of Immunoassay-Based Tools for the Comprehensive Quantification of Aβ40 and Aβ42 Peptides in Plasma. J Alzheimers Dis. 2016 Sep 6;54(2):751-62. PubMed.

    View all comments by Pedro Pesini

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