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Improving Alzheimer’s Disease (AD) diagnosis is the first essential step for improving patient care and quality of life. Early, accurate diagnosis is instrumental in giving people with AD and their families access to support, and the ability to participate in their own care decisions1.

Currently, clinicians diagnose AD using a combination of symptom presentation, brain imaging, and the detection of CSF biomarkers for AD. Despite their effective diagnostic properties, brain imaging and CSF collection are burdensome and invasive to the patient, as they require exposure to radiation and/or lumbar puncture. In addition, they are costly, making them unsuitable for most primary and secondary care settings2.

This inaccessibility has left 50-70% of symptomatic AD patients without a correct and timely diagnosis, impacting quality of life, medical autonomy, and general wellbeing2.

There is an urgent need for easily accessible, time- and cost-effective diagnostic tools for AD. Researchers around the world are working to achieve ultrasensitive blood-based protein detection through a simple blood test, which is minimally invasive and rapid to perform. The development of highly sensitive, accurate assays and technologies are critical for this to be possible.

Where are we today with blood-based detection?

There is substantial evidence supporting the utility of blood biomarkers for AD diagnosis2. This may be especially useful in diagnosing early-stage AD, prior to cognitive symptom presentation4. Simple, non-invasive methods to assess key markers of neurodegeneration, inflammation, lipid metabolism, and other pathogenesis from biofluids would allow for repeated measures to aid in AD diagnosis, monitoring disease progression and assessing drug efficacy during clinical trials. Ongoing efforts continue to evaluate the usability of novel blood plasma biomarkers in these contexts.

Detecting Tau

Detection in CSF

There are several CSF biomarkers for AD which are routinely used in conjunction with cognitive exams and imaging techniques to diagnose patients. Amyloid beta (Aβ) and tau are both hallmark proteins of AD pathology, and both total (t-) Tau and phosphorylated (p-) Tau are detected through CSF5. P-tau epitopes are known accurate CSF biomarkers for AD diagnosis and their levels are highest in preclinical stages, aiding early detection of AD. p-Tau is defined by the National Institute on Aging and the Alzheimer’s Association (NIA-AA) in their consensus guidelines as a key CSF biomarker for AD research and increased CSF Tau levels have been shown to correlate with cognitive decline in AD patients6. Despite this, the invasiveness of CSF collection calls for a comparable alternative.

Detection in blood

Several research groups have developed ultrasensitive p-Tau assays for use as blood biomarkers for AD, including various tau isoforms p-Tau 181, p-Tau 217 and p-Tau 231. One important factor to consider for increased plasma levels of p-Tau variants as a readout of AD pathology is specificity. The ability to differentiate between neuropathological conditions is vital. In several large-scale clinic-based studies, this has been put to the test and p-Tau plasma levels have been shown to correlate with AD pathology and accurately differentiate AD from other neurodegenerative diseases with high diagnostic accuracy7-9.

Detecting NfL

Detection in CSF

Neurofilament light chain (NfL) is well-established as a measure of axonal injury in a multitude of neurological disorders and found to be elevated in mild cognitive impairment (MCI), which occurs early in AD pathogenesis10. Although not AD-specific, NfL is considered as one of the recognizable CSF biomarkers for AD and can help provide greater insight and stratification for diagnosis11,12.

Detection in blood

Detection of NfL in blood has been established using ultrasensitive assays and is well validated as biomarker associated with several neurological disorders13. Compared to other blood biomarkers associated with AD pathology, the elevation in blood NfL levels observed in AD patients is relatively modest. Because of this and its lack of AD-specificity, plasma NfL may need to be used in conjunction with other biomarkers for AD. Research groups are finding novel support for the use of plasma p-tau181 combined with NfL as an accessible, minimally invasive biomarker to track AD progression14. Nonetheless, increases of plasma NfL is correlated with Aβ-PET and Tau-PET positivity, as well as with MRI-assessed neurodegeneration; further strengthening a case for a combined approach to blood-based monitoring for AD 15.

Detecting GFAP

Detection in CSF

Glial fibrillary acidic protein (GFAP) is strongly expressed in astrocytes, which are known players in AD pathogenesis. Playing important roles in clearing toxic proteins, GFAP is often used in research as an astrocyte-specific marker to study activation in response to injury or insult. It has beenshown that CSF levels of GFAP are consistently altered in individuals with AD16.

Detection in blood

Preliminary studies have found that the amount of GFAP in the blood is indicative of amyloid pathology in the brain17. In fact, recent research demonstrated that plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP, suggesting that plasma GFAP may be a sensitive biomarker for detecting Aβ pathology even among individuals in the early stages of AD18. Another recent student demonstrated that plasma GFAP levels could effectively discriminate participants stratified by clinical diagnosis and brain amyloid status and were predictive of future functional decline19.

Detecting SNAP-25

Detection in CSF

Synaptic dysfunction and degeneration are fundamental to AD pathophysiology and have been found to be associated with cognitive decline. Studying synaptosomal-associated proteins (SNAPs), like SNAP-25, that reflect synaptic degeneration are important for the development of novel CSF biomarkers for AD. Currently, research has shown CSF levels of SNAP-25 increase in relation to amyloid pathology in AD and CSF SNAP-25 can be used to discriminate between AD and other non-AD neurodegenerative diseases, suggesting potential for good diagnostic performance in line with other emerging CSF biomarkers for AD 20,21.

Detection in blood

While in CSF detection of synaptic proteins may be a useful indicator of cognitive decline and protein pathology, SNAP-25 detection in blood is in its infancy. Studies comparing CSF- and blood-derived independent samples suggest that even the most sensitive assays on the market lack the analytical sensitivity required for quantification of SNAP-25 in plasma20. This highlights an unmet need for the development of ultrasensitive assay technologies capable of detecting SNAP-25 reliably, accurately, and quickly from blood.

The future of blood-based protein biomarkers

Despite CSF and PET measures having excellent diagnostic properties, they are invasive, costly, and can be inaccessible. Using blood-based biomarkers as a screening tool for AD pathology has the advantage of being less invasive, more affordable, and more feasible at the primary care levels where most individuals will present with cognitive symptoms2. Once an idea, blood-based biomarkers for AD are becoming a reality. Study by study, research group by research group, and trial by trial — progress over the last decade towards CSF biomarkers for AD has surpassed scientific expectations and brings hope for future advancements from plasma. Most recently, the National Institute on Aging (NIA) and the Alzheimer’s Association (AA) proposed new AD diagnostic criteria to incorporate the use of blood-based biomarkers.

While our understanding of AD pathology and the role of fluid biomarkers has progressed, it would not have been possible without ultrasensitive protein biomarker detection technology.

Simoa® and AD Research

QuanterixSimoa® Technologies is raising the diagnostics bar by lowering the detectable biomarker limit. As leaders in this space, their ultra-sensitive Simoa® technology offers flexible immunoassays that support accurate detection of disease biomarkers in CSF and blood.

What is Simoa®? The single-molecule array (Simoa®) technology offered by Quanterix is a digital immunoassay technique. This novel solution is being implemented across oncology, neurology, cardiology, inflammation, and infectious disease disciplines.

As a protocol with minimal incubation times, these assays are both time- and cost-effective. Quanterixis at the cutting edge of assay sensitivity and accuracy, without compromising in-lab efficiency.

SimoaⓇ technology is positioned to transform pre-clinical and clinical research and improve the future of AD diagnostics. Be part of the revolution.

References

1. NIA, National Institute on Ageing. “How Is Alzheimer’s Disease Diagnosed?” U.S. Department of Health and Human Services, accessed on 08/11/2022, https://www.nia.nih.gov/health/how-alzheimers-disease-diagnosed.

1. Hansson O, Edelmayer RM, Boxer AL, et al. The Alzheimer’s Association appropriate use recommendations for blood biomarkers in Alzheimer’s disease. Alzheimers Dement. 2022;18(12):2669-2686. doi:10.1002/alz.12756

1. Brookmeyer R, Abdalla N, Kawas CH, Corrada MM. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement. 2018;14(2):121-129. doi:10.1016/j.jalz.2017.10.009

1. Cullen NC, Leuzy A, Janelidze S, et al. Plasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations. Nat Commun. 2021;12(1):3555. Published 2021 Jun 11. doi:10.1038/s41467-021-23746-0

1. Ashton NJ, Benedet AL, Pascoal TA, et al. Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease. EBioMedicine. 2022;76:103836. doi:10.1016/j.ebiom.2022.103836

1. Skachokova Z, Martinisi A, Flach M, et al. Cerebrospinal fluid from Alzheimer’s disease patients promotes tau aggregation in transgenic mice. Acta Neuropathol Commun. 2019;7(1):72. Published 2019 May 7. doi:10.1186/s40478-019-0725-3

1. Coomans EM, Verberk IMW, Ossenkoppele R, et al. A Head-to-Head Comparison Between Plasma pTau181 and Tau PET Along the Alzheimer’s Disease Continuum. J Nucl Med. 2023;64(3):437-443. doi:10.2967/jnumed.122.264279

1. Thijssen EH, Verberk IMW, Kindermans J, et al. Differential diagnostic performance of a panel of plasma biomarkers for different types of dementia. Alzheimers Dement (Amst). 2022;14(1):e12285. Published 2022 May 15. doi:10.1002/dad2.12285

1. Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020;324(8):772-781. doi:10.1001/jama.2020.12134

1. Zetterberg H, Skillbäck T, Mattsson N, et al. Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression. JAMA Neurol. 2016;73(1):60-67. doi:10.1001/jamaneurol.2015.3037

1. Mattsson-Carlgren N, Grinberg LT, Boxer A, et al. Cerebrospinal Fluid Biomarkers in Autopsy-Confirmed Alzheimer Disease and Frontotemporal Lobar Degeneration. Neurology. 2022;98(11):e1137-e1150. doi:10.1212/WNL.0000000000200040

1. Vrillon A, Ashton NJ, Karikari TK, et al. Comparison of CSF and plasma NfL and pNfH for Alzheimer’s disease diagnosis: a memory clinic study [published online ahead of print, 2023 Nov 11]. J Neurol. 2023;10.1007/s00415-023-12066-6. doi:10.1007/s00415-023-12066-6

1. Ashton NJ, Janelidze S, Al Khleifat A, et al. A multicentre validation study of the diagnostic value of plasma neurofilament light. Nat Commun. 2021;12(1):3400. Published 2021 Jun 7. doi:10.1038/s41467-021-23620-z

1. Moscoso A, Grothe MJ, Ashton NJ, et al. Longitudinal Associations of Blood Phosphorylated Tau181 and Neurofilament Light Chain With Neurodegeneration in Alzheimer Disease. JAMA Neurol. 2021;78(4):396-406. doi:10.1001/jamaneurol.2020.4986

1. Mattsson N, Cullen NC, Andreasson U, Zetterberg H, Blennow K. Association Between Longitudinal Plasma Neurofilament Light and Neurodegeneration in Patients With Alzheimer Disease [published correction appears in JAMA Neurol. 2019 Jun 10;:]. JAMA Neurol. 2019;76(7):791-799. doi:10.1001/jamaneurol.2019.0765

1. Bellaver B, Ferrari-Souza JP, Uglione da Ros L, et al. Astrocyte Biomarkers in Alzheimer Disease: A Systematic Review and Meta-analysis [published online ahead of print, 2021 May 5]. Neurology. 2021;10.1212/WNL.0000000000012109. doi:10.1212/WNL.0000000000012109

1. Pereira JB, Janelidze S, Smith R, et al. Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer’s disease. Brain. 2021;144(11):3505-3516. doi:10.1093/brain/awab223

1. Benedet AL, Milà-Alomà M, Vrillon A, et al. Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum. JAMA Neurol. 2021;78(12):1471-1483. doi:10.1001/jamaneurol.2021.3671

1. Yang Z, Sreenivasan K, Toledano Strom EN, et al. Clinical and biological relevance of glial fibrillary acidic protein in Alzheimer’s disease. Alzheimers Res Ther. 2023;15(1):190. Published 2023 Nov 3. doi:10.1186/s13195-023-01340-4

1. Nilsson J, Ashton NJ, Benedet AL, et al. Quantification of SNAP-25 with mass spectrometry and Simoa: a method comparison in Alzheimer’s disease. Alzheimers Res Ther. 2022;14(1):78. Published 2022 Jun 4. doi:10.1186/s13195-022-01021-8

1. Kivisäkk P, Carlyle BC, Sweeney T, et al. Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer’s disease. Alzheimers Res Ther. 2022;14(1):58. Published 2022 Apr 23. doi:10.1186/s13195-022-01002-x