The number of people living with Alzheimer’s disease is increasing in our aging population,1 highlighting the need for improved diagnostic criteria to identify the disease before the onset of dementia. Both positron-emission tomography (PET) imaging and cerebrospinal fluid (CSF) measurement of biomarkers are currently used to identify Alzheimer’s disease pathophysiology since they reflect the key aspects of disease pathology: neuronal and axonal degeneration; phosphorylation of tau with tangle formation; and oligomerization, aggregation and deposition of the 42 amino acid isoform (Aβ42) of β-amyloid into plaques.2,3 These biomarkers include total tau (T-tau), phosphorylated tau (P-tau) and Aβ42, and have been shown to have high diagnostic accuracy.4 However, PET imaging is very expensive and only accessible in specialised centres, and therefore unlikely to become a routine diagnostic tool in the assessment of high numbers of patients presenting with cognitive symptoms. Furthermore, lumbar puncture to obtain CSF is complicated, time-consuming and invasive. Therefore, there remains a need for easier, quicker, and more affordable diagnostic methods. A sensitive and specific blood test would be a more practical approach.
The most studied approach to developing blood biomarkers has been to measure the established brain biomarkers in blood samples. Until recently, this has not been possible since these proteins are present in much lower concentrations in blood than in CSF, for example, the CSF level of tau is around 2–300 pg/mL but the plasma level is around 5 pg/mL.5 In the last decade, technological advances have led to the development of ultrasensitive measurement techniques, such as the immuno-magnetic reduction and Single-molecule array methods, that have facilitated research into biomarkers in blood samples.6 These advances were reflected in a number of presentations at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD), which was held from March 26–31, 2019, in Lisbon, Portugal.
A presentation by Kaj Blennow of the University of Gothenburg, Sweden, highlighted recent progress in the measurement of the established CSF biomarkers in blood. The plasma Aβ42/40 ratio has been measured in blood and shows good agreement with brain amyloid measured by PET. Immunoassays have allowed the measurement of T-tau and P-tau in plasma. In addition, ultrasensitive immunoassays have facilitated the measurement of the axonal protein neurofilament light in blood samples, which may provide a tool to monitor the effects of investigational drugs on neurodegeneration.7
An important requirement of a blood-based biomarker assay for Alzheimer’s disease is the ability to detect the disease at an early stage before amyloid plaques and NFT become prevalent. Kim et al presented a study evaluating the clinical utility of the Multimer Detection System-Aβ oligomerization (MDS-OAβ) test, which measures Aβ oligomer levels in the blood. The test showed good correlation with CSF biomarkers and amyloid PET scans in patients with early stage Alzheimer’s disease, and has received regulatory approval in Korea.8
A novel non-immune based method of detecting biomarkers in blood is also in development. This method is based on thioflavin T, a fluorescent dye that is specific for beta sheet-rich secondary protein structure, and fluorescence correlation spectroscopy, an analytical method that has single-molecule sensitivity. While at an early stage of development, this technique has the potential to provide a cost-effective means of determining early amyloidogenic nanoplaques.9
The use of artificial intelligence is facilitating the use of testing methods suitable for large-scale screening. Another presentation described a machine-learning based prediction of CSF tauopathy using blood-biomarkers, based on data from 321 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.10 This showed greater correlation with CSF tau than a previous measure of plasma tau.11
In addition to established biomarkers, a new generation of biomarkers are in clinical development that represent different pathological process in Alzheimer’s disease. Astrocytes are essential for normal brain function and astrocyte reactivity is an early feature of Alzheimer’s disease. Glial fibrillary acidic protein (GFAP) is the major intermediate filament protein in astrocytes, and therefore has the potential to be a biomarker of Alzheimer’s disease. A pilot study measured GFAP in the serum and CSF of patients with Alzheimer’s disease (n=28), behavioural variant of frontotemporal dementia (bvFTD; n=35), Parkinson´s disease (PD; n=11), dementia with Lewy bodies/PD dementia (DLB/PDD; n=19) and controls (n=34). The levels of GFAP were significantly elevated in Alzheimer’s disease and DLB/PDD compared with controls, PD and bvFTD.12 Since assays for GFAP are commercially available, this method could be easily incorporated into clinical practice.
Another study has suggested that specific endogenous amyloid antibodies may serve as biomarkers for disease onset. Each antibody displays a unique pattern of amino acids that it recognises and this pattern can be used as a fingerprint to identify the antibody in human serum. Investigators screened 104 serum samples from people with Alzheimer’s disease and 104 samples from healthy controls. The unique patterns of 8–10 amyloid antibodies were significantly elevated in people with Alzheimer’s disease and were stable over 2–3 years.13
The high cost, insufficient accessibility and invasiveness of CSF assays limit their utility as screening tools for Alzheimer’s disease. There is a need for a multistage approach to screening. A blood test can fit into the current infrastructure and be used to rule out patients who do not need further workup. While the studies presented in Lisbon were all small and the results require validation in larger cohorts, these presentations have shown that the use of blood-based biomarkers is feasible for the imaging of early stage Alzheimer’s disease. Blood-based biomarkers could potentially serve as the first step in a multi-step process, similar to procedures used in other diseases, to aid the detection and treatment of this destructive disease as quickly as possible.
1. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019; DOI:https://doi.org/10.1016/S1474-4422(18)30454-X [Epub ahead of print].
2. Selkoe DJ. Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol. 2004;6:1054–61.
3. Grundke-Iqbal I, Iqbal K, Quinlan M, et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem. 1986;261:6084–9.
4. Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol. 2003;2:605–13.
5. Blennow K. A review of fluid biomarkers for Alzheimer’s disease: moving from CSF to blood. Neurol Ther. 2017;6:15–24.
6. Andreasson U, Blennow K, Zetterberg H. Update on ultrasensitive technologies to facilitate research on blood biomarkers for central nervous system disorders. Alzheimers Dement (Amst). 2016;3:98–102.
7. Blennow K. The expanded AD fluid biomarker toolbox – performance for diagnostics. Presented at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD) 26–31 March 2019, Lisbon, Portugal.
8. Kim S, An S, Youn Y, et al. A blood test of amyloidopathy for early diagnosis of Alzheimer’s disease. Presented at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD) 26–31 March 2019, Lisbon, Portugal.
9. Tilmann A, Jarvet J, Gräslund A, et al. Detection of amyloidogenic nanoplaques in the blood serum of patients with Alzheimer’s disease using methods with single-molecule sensitivity. Presented at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD) 26–31 March 2019, Lisbon, Portugal.
10. Petersen RC, Aisen PS, Beckett LA, et al., Alzheimer’s Disease Neuroimaging Initiative (ADNI): clinical characterization, Neurology, 2010;74:201-9.
11. Swan A, Scheiber C, Faux N, et al. Using blood-based biomarkers to predict CSF tautopathy. Presented at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD) 26–31 March 2019, Lisbon, Portugal.
12. Oecki P, Halbgebauer S, Aderi-Straub S, et al. Glial fibrillary acidic protein in serum is increased in Alzheimer’s disease and correlates with cognitive impairment. Presented at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD) 26–31 March 2019, Lisbon, Portugal.
13. Glabe C, Nakajima R, Jasinskas A, et al. Endogenous human antibodies that are correlated with Alzheimer’s disease. Presented at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD) March 26-31, 2019, Lisbon, Portugal.
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