7


APP669-711/Aβ1-42 ratio and Aβ1-40/Aβ1-42 ratio (a well-known biomarker) also improved AUC values to 96.7% in the Japanese dataset and 94.1% in the Australian dataset. The concentration of Aβ1-42 in CSF is known to decrease when Aβ accumulates in the brain, a phenomenon that was similarly identifi ed in the data, with reduced plasma levels of Aβ1-42 in amyloid PET-positive cases. This change of Aβ1-42 may be caused by Aβ1-42 being trapped in the brain, which lowers the amount of Aβ1- 42 available to enter bodily fl uids.


Figure 3. Mass spectrum of plasma Aβ peptides detected by MALDI-TOF MS.


This resulted in the fi rst successful detection of endogenous Aβ1-42 and Aβ1-40 in human plasma by MS and simultaneously produced other discoveries only available using MS (Figure 3) [7, 8]. Specifi cally, MS revealed the presence of many Aβ species other than Aβ1-42 and Aβ1-40 in human plasma, including APP669-711 with an N-terminus elongated beyond Aβ1-x (Figure 4). In this IP-MS procedure using MALDI- TOF MS, the Aβ species after IP is directly applied to MALDI-TOF MS without protease digestion. This makes it possible to save the sample preparation time and measure intact Aβ species present in plasma.


ROC analysis of the blood concentration of Aβ1-42 alone also showed AUC values of 87.2% (Japanese dataset) and 75.7% (Australian dataset), indicating Aβ1-42 alone was inadequate as a biomarker, though these AUC values increased when Aβ1-42 concentration was taken as a ratio of other Aβ species. This increase in AUC is probably due to individual variations in the total concentration of all Aβ species in the blood, which lowers the effectiveness of using absolute Aβ1-42 concentration alone as a biomarker. Taking Aβ1-42 as a ratio of another Aβ species may suppress the infl uence of this individual variation in total Aβ. This report published in 2018 showed a high concordance between plasma Aβ measured by IP-MS and amyloid PET and served as a trigger for the recognition of blood Aβ as a useful biomarker by researchers worldwide.


Less invasive biomarkers refl ecting AD pathology lead the way to AD drug discovery


Amyloid MS technique can measure unique APP669-711/Aβ1-42 ratio as well as Aβ1-40/Aβ1-42 ratio in plasma. The Aβ composite biomarker created by combining the two Aβ ratios demonstrated high accuracy in distinguishing amyloid PET-positive cases from amyloid PET-negative cases. Biomarkers that refl ect AD pathology are essential to AD drug discovery, diagnosis and staging, and blood-based biomarkers that provide a less invasive means of measuring large numbers of specimens will become increasingly useful.


Table 1. Table 1 Performance of plasma Aβ biomarkers. Biomarker Figure 4. Plasma Aβ peptides detected by IP-MS. Extensive blood-based biomarker studies


The research for an Aβ biomarker by IP-MS commenced in 2013 in cooperation with Japan’s National Center for Geriatrics and Gerontology. This biomarker discovery study using IP-MS and amyloid PET imaging with PIB (62 cases) detected a higher ratio of APP669-711 to Aβ1-42 (APP669-711/Aβ1-42) in plasma from amyloid PET-positive patients (Figure 5) [9]. Receiver operating characteristic (ROC) analysis of the APP669- 711/Aβ1-42 ratio for amyloid PET-positive patients also showed a high area under the curve (AUC) value of 96.9 %. The APP669-711/Aβ1-42 ratio was also signifi cantly correlated with the standardised uptake value ratio (SUVR) of amyloid PET, with a correlation coeffi cient of 0.687 (p < 0.001). Based on this data, a high concordance between plasma APP669-711/Aβ1-42 ratio and amyloid PET was reported for the fi rst time in 2014.


Insuffi cient reproducibility is a common issue with newly discovered blood-based biomarkers that often leads to their abandonment. Therefore, the blood-based biomarker required a validation using specimens that were entirely independent of those used in the discovery study. A validation study was conducted in two datasets from Japan’s National Center for Geriatrics and Gerontology and the Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL). ROC analysis of the APP669-711/ Aβ1-42 ratio for amyloid PET-positive cases (using the PIB tracer) revealed a high AUC value of 92.3% in the Japanese dataset (121 cases) and 89.5% in the Australian dataset (111 cases) (Table 1) [10]. A composite biomarker created by combining


APP669-711/Aβ1-42 Aβ1-42


Evaluation AUC


Sensitivity Specifi city Accuracy AUC


Sensitivity Specifi city Accuracy AUC


Aβ1-40/Aβ1-42


Sensitivity Specifi city Accuracy AUC


composite biomarker


Sensitivity Specifi city Accuracy


NCGG (n=121) 87.2% 74.0% 88.7% 82.6% 92.3% 68.0% 91.5% 81.8% 96.7% 96.0% 87.3% 90.9% 96.7% 86.0% 88.7% 87.6%


AIBL (n=111) 75.7% 78.3% 66.7% 73.0% 89.5% 86.7% 74.5% 81.8% 88.9% 90.0% 70.6% 81.1% 94.1% 91.7% 82.4% 87.4%


References


1. Villemagne V.L. et al. (2013). Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 12 (4): 357–367.


2. Janelidze S. et al. (2021). Head-to-head comparison of 8 plasma amyloid-β 42/40 assays in Alzheimer disease. JAMA Neurol. 78 (11): 1375–1382.


3. Brand A.L. et al. (2022). The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer’s disease: a literature review. Alzheimers Res Ther. 14 (1): 195.


4. Winston C.N. et al. (2023). Evaluation of Blood-Based Plasma Biomarkers as Potential Markers of Amyloid Burden in Preclinical Alzheimer’s Disease. J Alzheimers Dis. 92 (1): 95–107. doi: 10.3233/JAD-221118. PMID: 36710683.


5. Shanthi K.B. et al. (2015). A systematic review and meta-analysis of plasma amyloid 1-42 and tau as biomarkers for Alzheimer’s disease. SAGE Open Med. 3: 2050312115598250.


6. Wang R. et al. (1996). The profi le of soluble amyloid beta protein in cultured cell media. Detection and quantifi cation of amyloid beta protein and variants by immunoprecipitation-mass spectrometry. J Biol Chem. 271 (50): 31894–31902.


7. Kaneko N. et al. (2014). Identifi cation and quantifi cation of amyloid beta-related peptides in human plasma using matrix-assisted laser desorption/ionization time-of-fl ight mass spectrometry. Proc Jpn Acad Ser B Phys Biol Sci. 90 (3): 104–117.


8. Korecka M., Shaw L.M. (2021). Mass spectrometry-based methods for robust measurement of Alzheimer’s disease biomarkers in biological fl uids. 159 (2): 211–233.


Figure 5, Difference of plasma Aβ peaks on MALDI-TOF mass spectra between amyloid PET-positive and PET-negative cases.


9. Kaneko N. et al. (2014). Novel plasma biomarker surrogating cerebral amyloid deposition. Proc Jpn Acad Ser B Phys Biol Sci. 90 (9): 353–364.


10. Nakamura A. et al. (2018). High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 554 (7691): 249–254.


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