Alzheimer’s disease (AD) is one of the most prominent and well-known progressive neurodegenerative conditions that affect humanity.
It is a form of dementia related to excessive levels of proteins such as tau and amyloid-beta in certain brain regions. Treatment for AD is gradually becoming more and more effective; with many more patients capable of living more or less normal lives while managing their conditions over time.
Rapid diagnosis and treatment of Alzheimer’s
Treatment benefits to help those with this condition may be most profound if a diagnosis is made as soon after the onset of AD as possible. Clinicians may also prefer to gain a picture of the probability that a currently healthy patient will go on to develop the condition in the future, particularly in the case of people with a family history of AD.
Brain imaging has become the ideal standard of diagnosis and risk assessment in AD. The main alternative is the analysis of cerebrospinal fluid, which needs to be sampled from inside the spinal cord. This is a risky and potentially painful procedure that is not compatible with the possibility that routine testing may become necessary for patients with known AD risk factors.
The imaging options, on the other hand, involve positronic-emission tomography (PET) enhanced by infusing the patient’s system with mildly radioactive molecules that light up when they bind AD biomarkers in the brain. These biomarkers include amyloid-beta, a nervous-system protein that becomes over-expressed in the course of the condition and is likely to contribute to AD disease activity.
Amyloid-beta is produced when its larger precursor molecule is broken down into smaller fragments of 40 or 42 amino acids in length (known as Aβ40 or Aβ42). APP, as the precursor is known, may also contribute to AD risk, especially in terms of how its concentrations compare to that of either Aβ42 or Aβ40.
However, PET imaging studies mainly concentrate on where fully-formed and disease-related Aβ is in the brain, and on classic aggregation patterns (which often, but not always, involve the same specific regions) that indicate pre-clinical or as-yet symptomless AD.
Therefore, patients may require a series of repeat imaging sessions in which Aβ activity is tracked over time. Accordingly, despite the relatively convenient and non-invasive nature of PET, diagnoses that incorporate it may delay the development of treatment plans, and also preclude some patients from entry into new anti-AD clinical trials in some cases.
Repeated injections of Aβ-highlighting radio-markers may not be acceptable to some patients, especially those of advanced age or disease status who may be uncomfortable or confused in medical settings. In addition, PET may be resource-intensive, especially in the case of newer modalities. Therefore, a more cost- and time-effective option for AD risk testing is desirable.
Developing blood tests for Alzheimer’s disease
Researchers have known for some time that APP, Aβ40 and Aβ42 are also present in the bloodstream, and that their plasma concentrations may relate to those in the brain. Therefore, it should be possible to test blood samples for these AD biomarkers. Unfortunately, the clinical trials that have attempted to develop protocols that measure plasma Aβ in the lab into fully-functional blood tests have been unconvincing to date.
Examples of these studies have involved ELISAs, or assays in which labelled antibodies are engineered to bind the Aβ present in samples, thus quantifying it. Others have used liquid chromatography in conjunction with quantification methods such as mass spectroscopy to determine plasma amyloid levels. However, these methods have encountered failure for various reasons. These have included a weak sensitivity for Aβ that could not compete with that of CSF assays; the inability to distinguish high-risk individuals from those with lower AD risks, or the inability to do the same despite being able to predict increased brain Aβ aggregation.
However, a new assay for plasma Aβ has now been reported to be closely associated with its levels in the brains of a cohort of participants from large-scale AD risk studies. The new form of blood test has also combined the values of Aβ40, Aβ42 and the APP fragment APP669-711 and converted these into ratios of each other. This resulted in the variables Aβ40/Aβ42, APP669-711/Aβ42 and a composite score of both, which enhanced the detection of AD risk. This new, comprehensive plasma Aβ test enabled the team behind it to predict disease risks in a de novo sample of potential patients. The blood test involved in this study is also based on conventional, well-validated protocols employed in both academic and clinical settings. They were immunoprecipitation, which enhances the detection of proteins such as Aβ and APP; and MALDI-TOF mass spectroscopy, which (again) quantifies the concentrations found in samples.
The researchers were a team collaborating across institutions in Japan and Australia, and led by Katsuhiko Yanagisawa of the Japanese national centre for geriatrics and gerontology (NCGG). They used the Aβ40, Aβ42 and APP fragment datasets (measured using PET) built to assess AD risks: the NCGG dataset (n=121) and the AD-related subset of the Australian Imaging, Biomarker and Lifestyle Study of Ageing (AIBL, n=252) to establish that their ratio- and composite-based Aβ protein values were significantly associated with the risk of AD. These associations were robust across both datasets, which included patients, non-patients with disease risks and people with no AD risks as participants.
This analysis also showed that the biomarkers detected using the new blood test were highly correlated with actual brain Aβ aggregation (as measured using PET) and Aβ42 concentrations from CSF assays. The team then applied the same analysis to a de novo clinical dataset based on results from 31 AD patients and 20 similar people without AD diagnoses. Again, the biomarker values appeared to predict AD risk, with a sensitivity of nearly 97%, an accuracy of approximately 90% and a specificity of 81%. Therefore, the team argues that their new blood test should be put to use in the validation of these findings using even bigger datasets with a more global representation.
The team also concedes (in their paper published in Nature on the 31st of January 2018) that their immunoprecipitation/MALDI-TOF assay also requires improved scaling and automation for real-world clinical applicability. However, they also argue that such a blood test could enhance AD risk assessments and conserve the use of imaging in the future. The team also asserts that their blood test could help more people gain eligibility for clinical trials, which often only admit those with very early-stage AD. I
n conclusion, this study may have established that amyloid-beta and its precursor are subject to a potential routine blood test, and that their ratios are usable clinical biomarkers that correlate with imaging studies for their accumulation in the brains of patients with AD.
Top image: Old people’s home. (Public Domain)
Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018.
Wang J, Gu BJ, Masters CL, Wang YJ. A systemic view of Alzheimer disease - insights from amyloid-beta metabolism beyond the brain. Nature reviews Neurology. 2017;13(10):612-23.