CN-122029617-A - Protein markers for neurodegenerative diseases

Abstract

Diagnostic and therapeutic methods based on plasma protein markers for neurodegenerative diseases, such as Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD), and kits for diagnosing and/or treating these conditions are provided. Also provided are machine learning systems and methods for assessing risk of a subject suffering from a neurodegenerative disease based on measured protein marker levels.

Inventors

• YE YURU
• FU JIEYU
• YE CUIFEN
• JIANG YUANBING
• OUYANG LI

Assignees

• 香港科技大学
• 香港神经退行性疾病中心有限公司

Dates

Publication Date

20260512

Application Date

20250901

Priority Date

20240909

Claims (20)

1. 1. A method of assessing the risk of a neurodegenerative disease accompanied by an amyloid pathology in an individual comprising: Calculating an individual risk score based on p-Tau217 plus the concentration of any one or more of CD33, FAM3B, KYNU, and NELL1 in a biological sample from the individual, wherein a weighting coefficient (βi) is assigned to each protein, and using these coefficients and an intercept (ε) derived from training data comprising patients who have been diagnosed with the neurodegenerative disease and healthy controls not having the disease, to calculate the risk score, and The risk score is compared to a predetermined threshold to classify the risk of the individual as low risk, medium risk, or high risk.
2. 2. The method of claim 1, further comprising, prior to the calculating step, obtaining the biological sample from the individual and measuring the concentration of each of the proteins in the sample.
3. 3. The method according to claim 1, comprising: (1) By inputting a set of values into a formula To calculate individual risk scores, and (2) An individual having a risk score below 28 is determined to be at low risk for the neurodegenerative disease with cerebral amyloid pathology, an individual having a risk score above a value of 45 is determined to be at high risk for the neurodegenerative disease with cerebral amyloid pathology, and an individual having a risk score of 28 to 45 is determined to be at moderate risk for the neurodegenerative disease with cerebral amyloid pathology, Wherein the set of values comprises p-Tau217 plus plasma, serum or whole blood levels of any one or more of CD33, FAM3B, KYNU and NELL1, And obtaining the weighting coefficient (β i ) and intercept (ε) of each protein from the plasma, serum or whole blood level of each protein in a subject group diagnosed with neurodegenerative disease or a healthy control subject group using the following logistic regression model (neurodegenerative disease=1; healthy control=0): 。
4. 4. The method of claim 1, wherein the neurodegenerative disease is Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).
5. 5. The method of claim 1, wherein the weighting coefficients (β i ) and intercept (ε) of each protein are shown in table 2.
6. 6. A method of assessing the risk of cerebral amyloid pathology in an individual who has been diagnosed with a neurodegenerative disease, comprising: Calculating an individual risk score for a cerebral amyloid pathology based on p-Tau217 plus the concentration of any one or more of CD33, FAM3B, KYNU, and NELL1 in a biological sample from the individual, wherein a weighting coefficient (βi) is assigned to each protein and the risk score is calculated using these coefficients and an intercept (epsilon) derived from training data comprising a diagnosed patient who has been diagnosed with a neurodegenerative disease with a cerebral amyloid pathology and a control subject who has been diagnosed with the neurodegenerative disease but not with a cerebral amyloid pathology, and The risk score is compared to a predetermined threshold to classify the risk of the individual's brain amyloid pathology as low risk, medium risk or high risk.
7. 7. The method of claim 6, further comprising, prior to the calculating step, obtaining the biological sample from the individual and measuring the concentration of each of the proteins in the sample.
8. 8. The method as claimed in claim 6, comprising: (1) By inputting a set of values into a formula To calculate individual risk scores, and (2) Individuals with risk scores below 28 were determined to be at low risk for cerebral amyloid pathology, individuals with risk scores above 45 were determined to be at high risk for cerebral amyloid pathology, and individuals with risk scores of 28 to 45 were determined to be at moderate risk for cerebral amyloid pathology, Wherein the set of values comprises p-Tau217 plus plasma, serum or whole blood levels of any one or more of CD33, FAM3B, KYNU and NELL1, And obtaining the weighting coefficient (β i ) and intercept (ε) of each protein from the plasma, serum or whole blood level of each protein in a subject group diagnosed with neurodegenerative disease or a healthy control subject group using the following logistic regression model (neurodegenerative disease=1; healthy control=0): 。
9. 9. the method of claim 6, wherein the neurodegenerative disease is Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).
10. 10. The method of claim 6, wherein the weighting coefficients (βi) and intercept (ε) for each protein are shown in Table 2.
11. 11. A method of assessing the risk of a neurodegenerative disease with brain amyloid pathology in two individuals comprising: (1) By inputting a set of values into a formula And (3) calculating a risk score for each individual (2) A first individual having a risk score lower than a risk score of a second individual is determined to be at lower risk for the neurodegenerative disease with amyloid pathology, Wherein the set of values comprises p-Tau217 plus plasma, serum or whole blood levels of any one or more of CD33, FAM3B, KYNU and NELL1, And obtaining the weighting coefficient (β i ) and intercept (ε) of each protein from the plasma, serum or whole blood level of each protein in a subject group diagnosed with neurodegenerative disease or a healthy control subject group using the following logistic regression model (neurodegenerative disease=1; healthy control=0): 。
12. 12. the method of claim 11, wherein the neurodegenerative disease is Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).
13. 13. The method of claim 11, wherein the weighting coefficients (βi) and intercept (epsilon) for each protein are shown in table 2.
14. 14. A method of assessing progression of a neurodegenerative disease with brain amyloid pathology in an individual, comprising: (1) By inputting a set of values into a formula Calculating a first risk score for an earlier time; (2) Repeating step (1) at a later time to calculate a second risk score, and (3) Determining that the individual having the second risk score higher than the first risk score is suffering from a worsening neurodegenerative disease with amyloid pathology, and determining that the individual having the second risk score not higher than the first risk score is suffering from a stable or non-progressive neurodegenerative disease with amyloid pathology, Wherein the set of values comprises p-Tau217 plus plasma, serum or whole blood levels of any one or more of CD33, FAM3B, KYNU and NELL1, And determining the weighting coefficient (β i ) and intercept (ε) of each protein from the plasma, serum or whole blood level of each protein in a subject group diagnosed with neurodegenerative disease or a healthy control subject group using the following logistic regression model (neurodegenerative disease=1; healthy control=0): 。
15. 15. the method of claim 14, wherein the neurodegenerative disease is Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).
16. 16. The method of claim 14, wherein the weighting coefficients (βi) and intercept (epsilon) for each protein are shown in table 2.
17. 17. A kit for assessing the risk of a neurodegenerative disease associated with brain amyloid pathology in an individual comprising a plurality of containers, each of said containers containing an agent capable of determining the plasma, serum or whole blood level of p-Tau217 plus any one or more of CD33, FAM3B, KYNU and NELL1 in said individual.
18. 18. The kit of claim 17, wherein the neurodegenerative disease is Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).
19. 19. A test chip for assessing the risk of a neurodegenerative disease associated with brain amyloid pathology in an individual comprising a solid substrate and reagents capable of determining the plasma, serum or whole blood levels of p-Tau217 plus any one or more of CD33, FAM3B, KYNU and NELL1 in said individual, wherein each reagent is immobilized at an addressable location on said substrate.
20. 20. The chip of claim 19, wherein the neurodegenerative disease is Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).

Description

Protein markers for neurodegenerative diseases RELATED APPLICATIONS The present application claims priority from U.S. provisional patent application No. 63/692,297 filed 9 at 2024, the contents of which are incorporated herein by reference in their entirety for all purposes. Background Alzheimer's Disease (AD) is one of the most common forms of dementia worldwide, accounting for 60-70% of all cases of dementia. It is an irreversible degenerative brain disease and is the leading cause of death in the elderly. The hallmark of this disease is the deposition of extracellular beta-amyloid (aβ) plaques and intracellular neurofibrillary tangles, which lead to decreased memory, reasoning, judgment and motor ability, and worsening symptoms over time. Currently 3500 tens of thousands of people worldwide are estimated to have AD. This figure is expected to rise significantly to 1 million by 2050 due to longer life expectancy. AD is incurable and the pathophysiology of the disease remains relatively unknown. The U.S. food and drug administration (US Food and Drug Administration, FDA) approves only five drugs for the treatment of AD, but these drugs only alleviate symptoms and cannot alter disease pathology because they cannot reverse the condition or prevent further exacerbation and are ineffective in severe conditions. Early diagnosis and early therapeutic intervention are therefore of vital importance in the management of AD. Studies have demonstrated that AD affects the brain well before the actual symptoms of memory loss or cognitive decline actually manifest. However, to date, there is no effective and reliable diagnostic tool for early detection of AD, and by the time patients are diagnosed with AD using standard methods currently in use (which involve subjective clinical assessment), pathological symptoms are already in advanced stages. The present disclosure provides high performance diagnostic methods that utilize one or more protein markers to assess the risk of neurodegenerative diseases, including AD, to aid in early diagnosis. Brief summary of the invention Neurodegenerative diseases are caused by progressive and often irreversible loss of neuronal structure and function, a process known as neurodegeneration and commonly found in the elderly population. Due to the lack of cure for neurodegenerative diseases and the destructive social and economic impact of such diseases, there is an urgent need for new, efficient and effective methods of early diagnosis that can then potentially support early intervention for these conditions. The present invention meets this and other related needs. In a first aspect, the invention provides a method of assessing the risk of a neurodegenerative disease with brain amyloid pathology in an individual. The method comprises the steps of first calculating a disease risk score for an individual based on the measured concentration of protein p-Tau217 in combination with any one or more of CD33, FAM3B, KYNU and NELL1 in a biological sample taken from the individual, wherein each protein is assigned a weighting coefficient (βi), and calculating a risk score using these coefficients and the intercept (epsilon) derived from training data, including a diagnostic patient that has been diagnosed with the disease and a healthy control that does not have a neurodegenerative disease with brain amyloid pathology. Second, the risk score from the first step is then compared to a predetermined threshold to classify the risk of the individual as low risk, medium risk, or high risk. In some embodiments, the method includes the steps of measuring the concentration of a protein in a biological sample from an individual, wherein the protein is p-Tau217 in combination with any one or more of CD33, FAM3B, KYNU, and NELL1, assigning a weighting coefficient (βi) to each measured protein concentration, calculating an individual risk score using the weighting coefficient (βi) and an intercept (ε) derived from training data including diagnostic patients and healthy controls, and comparing the calculated risk score to a predetermined threshold to classify the risk of the individual as low risk, medium risk, or high risk. Optionally, prior to the measuring step, there is a step of obtaining a biological sample from the individual. An exemplary method of the invention for assessing the risk of a neurodegenerative disease with brain amyloid pathology in an individual comprises the steps of (1) inputting a set of values into a formula And (2) determining an individual having a risk score below 28 as having a low risk for neurodegenerative disease with brain amyloid pathology, determining an individual having a risk score above 45 as having a high risk for neurodegenerative disease with brain amyloid pathology, and determining an individual having a risk score of 28 to 45 as having a moderate risk for neurodegenerative disease with brain amyloid pathology, wherein the set of values comprises p-Tau217 (e.g., plas