Three Progresses in the Diagnosis of Alzheimer's Disease

In the past year, Alzheimer's disease research has been receiving widespread attention from the industry and patients, especially after aducanumab received an unexpected and landmark approval
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The medical community generally believes that therapies based on the amyloid hypothesis can only be effective in the early stages of the disease.
Therefore, faster and simpler diagnostic strategies are needed to enable patients to obtain potentially improved disease treatments in the early stages of the disease course.

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Three major advances in the recent exploration of the diagnosis of Alzheimer's disease include: blood biomarker analysis, polygenic risk score, and non-invasive technology
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Blood biomarker analysis Molecular methods for diagnosing Alzheimer's disease and other dementias have traditionally focused on cerebrospinal fluid analysis
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This clear liquid, 99% of which is water, surrounds and fills the brain and spinal cord
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Although its main function is to buffer the brain from shocks, it also has a role to transport metabolites in the brain, which means that the analysis of cerebrospinal fluid can provide a window to understand the balance of brain chemicals
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Alzheimer’s disease researchers pointed out that beta amyloid levels are thought to play a key role in how the disease spreads through the brain.
By comparing the levels of the two forms of beta amyloid in the cerebrospinal fluid, it is possible to predict the amyloid of the brain itself.
Protein load level
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Specifically, compared with the form of 42 amino acids long (Aβ42) and 40 amino acids long (Aβ40), β amyloid (Aβ42) is reduced
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This is because Aβ42 tends to form insoluble plaques as the disease spreads throughout the brain
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Although this is a major improvement, it is still a major challenge to test the extremely small amount of cerebrospinal fluid in the human central nervous system with an average volume of only 150 ml
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However, research work in the past few years has shown that blood-based biomarker analysis can accurately detect the internal state of the brain through signals from the periphery of our brain.

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The new single-molecule level of detection can target neurodegeneration-related molecules, such as neurofilament light chain (neurofilament light chain)
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In 2020, researchers released new blood biomarker testing data used to determine the ratio of Aβ42/Aβ40, and then researchers published tau, another key biomarker for Alzheimer's disease.
Perfect analysis of the level
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The most exciting aspect of this research is that the two measurements can be combined to classify patients
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The high level of tau in plasma can be used as an indicator for doctors, indicating that patients may be eligible for clinical treatment of Alzheimer's disease, because tau protein is thought to begin to rise early in the course of the disease; while the tau result is negative, and the neurofilament light chain result If it is positive, it may prompt the doctor to diagnose non-Alzheimer's dementia
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Since changes in tau and neurofilament light chains may occur decades before symptoms appear, blood biomarkers may help patients get a diagnosis and get treatment when the drug treatment is most effective
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Polygenic risk score As we all know, the genetics of Alzheimer's disease is very complicated
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99% of Alzheimer's disease can not find the "culprit" gene
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Different genetic variants, called single nucleotide polymorphisms, have only a small risk of causing Alzheimer's disease
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Efforts to discover other risk factors rely on genome-wide association studies, in which millions of single nucleotide polymorphisms are associated with risk to assess specific diseases
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For "many changes, little effect" rule it has so far identified one exception is the APOE-ε4 allele of the APOE gene, which encodes apolipoprotein E
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Faced with this complex genetic map, the use of genome sequencing to diagnose Alzheimer’s disease has not been commonly used in clinical practice.

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However, if there is a more clear set of genetic risk factors, patients can be treated with classification several decades before the onset of symptoms, which has great clinical benefits for patients
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There was a major breakthrough in this field this year.
Researchers released a new method for calculating polygenic risk scores
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Polygenic risk score is a broad term used to describe the method of combining different risk genes into one number
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In this method, standardization is very difficult
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Researchers have great disagreements on the weights that should be given to different risks, such as how the risk of APOE-ε4 is measured, and even whether Alzheimer’s disease should be considered polygenic (many small genetic risks superimposed) or oligogenic ( The number of genetic mutations that cause risk is limited) diseases are still the focus of controversy
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Researchers from Belgian university KU Leuven and Dementia Research Institutes compared the accuracy of various polygenic risk scoring models and came up with the following key conclusions: Alzheimer's Murder’s disease should be modeled as a polygenic disease; age is a factor that must be considered when calculating the polygenic risk score-the elderly are unlikely to have the APOE-ε4 allele because this gene is related to the Alzheimer’s Murder disease and cardiovascular disease caused early death and shortened lifespan are closely related; the team also identified a specific polygenic risk scoring method
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Non-invasive technology Although the analysis of cerebrospinal fluid and blood biomarkers makes high-throughput screening possible, these tests will greatly accelerate the diagnosis of Alzheimer’s disease if they can be measured by non-invasive methods, such as saliva.
Or cheek swab analysis
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Although sampling of these bodily fluids is currently an approved test, there are also scientific studies linking oral microbes to Alzheimer's disease
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These studies are based on the fact that microorganisms such as Porphyromonas gingivalis may enter the brain to increase neuroinflammation or even directly damage neurons
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Compared with blood-based biomarker analysis, research focused on non-invasive analysis is still at a very early stage
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Although the goals of this study, such as proteins like Aβ42 and tau, are clear, the sample size of the study is too small
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The largest research conducted to date is an immunosorbent assay based on 70 Alzheimer's disease patients measuring Aβ42 levels in their saliva samples using enzyme-linked immunosorbent assay
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This study found that there was a small but statistically significant increase in the level of Aβ42 in the patient's saliva
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But this research is now ten years old, and the research on these traditional biomarkers of Alzheimer's disease has proved that the data obtained is not consistent
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Non-invasive methods may make the diagnosis of Alzheimer's disease very easy to use, but there are currently no convincing studies published that prove the reliability of this method
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Reference source: Three Advances in Alzheimer's Disease Diagnostics