Identifying subjects having or at risk of developing alzheimer's dementia

Abstract

In a first aspect, the present invention relates to a method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the method comprising: (a) determining in a first bodily fluid sample of the subject at least an amount of a compound having a mass of 110.0367 in grams / mole; (b) determining an amount of the same compound as in (a) in a second body fluid sample of the subject; (c) determining a change in the amount of the compound determined according to (a) compared to the corresponding amount of the compound determined according to (b); (d) analyzing the change determined in (c) using a computer-implemented prediction algorithm capable of predicting AD in the subject based on the compound, thereby identifying a subject having AD or at risk of developing Alzheimer's dementia if AD is predicted; wherein the first body fluid sample is obtained prior to administration of thietherazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administration of thietherazine or a pharmaceutically acceptable salt thereof to the subject.

Description

[0001] In a first aspect, the present invention relates to a method for identifying a patient suffering from Alzheimer's dementia. dementia (AD) or a subject at risk of developing Alzheimer's dementia, the method comprising: (a) determining in a first bodily fluid sample of the subject an amount of at least one compound having a mass in grams per mole selected from the group consisting of: 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.345, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.0452, 212.0536, 234.1832, 236.104 9, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 319.2486, 331.2545, 332.1372, 334.2146, 339.3135, 346.1528, 350.0956, 366.0912, 371.8758, 440.2751, 538.1752, 540.2563, and 782.5638 (Group 1); (b) analyzing the amount of at least one compound determined using a computer-implemented prediction algorithm that is capable of predicting AD in the subject based on the at least one compound, thereby identifying a subject who has AD or is at risk of developing Alzheimer's dementia if AD is predicted. In a second aspect, the present invention relates to a method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia. The third aspect of the present invention and the fourth aspect of the present invention both relate to a method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia. In a fifth aspect, the present invention relates to a second diagnostic use, and a sixth aspect of the present invention relates to a device suitable for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, and a seventh aspect of the present invention relates to a kit (kit) for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia. Background Art

[0002] The accumulation of proteins or protein fragments (peptides) in the brain is a prominent feature of age-related neurodegenerative diseases. In Alzheimer's disease (AD) and cerebral β-amyloid angiopathy (CAA), the aggregation of β-amyloid peptides (Aβ) is believed to trigger the disease. Regarding the treatment of AD, several active agents are known, such as, for example, Thiethylperazine [1]. Regarding diagnosis, the higher amounts of 40 and 42 amino acid Aβ peptides in the brain are partly reflected in the increase of these peptides in the peripheral blood flow and are used as diagnostic indicators for Alzheimer's disease. However, quantification of Aβ in blood samples is unreliable (even using extremely sensitive methods such as liquid chromatography-mass spectrometry (LC-MS / MS)) and requires Aβ immunoprecipitation as an additional and expensive step for sample preparation. Such an assay has recently become publicly available and has achieved an accuracy of about 77% in predicting AD-indicative brain amyloid status in patients in the 65-75 age group, with the accuracy decreasing with age [2]. Another study by E. Trushina et al. using UPLCToF-MS-based metabolomics analyzed and compared the metabolite profiles in plasma and CSF samples from cognitively normal probands, probands with mild cognitive impairment, and AD patients [3]. However, although early diagnosis is mentioned as a catchword, it should be noted that current studies are unable to do more than distinguish between healthy and diseased probands. In addition, since different metabolite markers were detected in plasma and CSF, there are other differences, such as which body fluid was examined.

[0003] However, since AD ​​pathology is hypothesized to begin as much as 20 years before the onset of clinical symptoms, diagnostic methods for detecting signs of AD pathology in younger populations are needed.

[0004] Therefore, the underlying technical problem is to provide means and methods for meeting the above needs, in particular to provide methods for diagnosing or prediagnosing Alzheimer's dementia in a subject.

[0005] Aspect 1 - for the identification of patients with or at risk of developing Alzheimer's dementia (AD) Methods for subjects at risk

[0006] Thus, in a first aspect, the present invention relates to a method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0007] (a) determining in a first bodily fluid sample of the subject an amount of at least one compound having a mass in grams per mole selected from the group consisting of: 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.345, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.0 452, 212.0536, 234.1832, 236.1049, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 319.2486, 331.2545, 332.1372, 334.2146, 339.3135, 346.1528, 350.0956, 366.0912, 371.8758, 440.2751, 538.1752, 540.2563 and 782.5638 (Group 1);

[0008] (b) analyzing the determined amount of the at least one compound using a computer-implemented prediction algorithm capable of predicting AD in the subject based on the at least one compound, thereby identifying the subject as having AD or at risk of developing Alzheimer's dementia if AD is predicted.

[0009] As used hereinafter, the terms "having", "comprising" or "including" or any of their arbitrary grammatical variations are used in a non-exclusive manner. Thus, these terms may refer both to a situation in which no other features are present in the entity described in this context other than the features introduced by these terms, and to a situation in which one or more other features are present. As an example, the expressions "A has B", "A comprises B" and "A includes B" may refer both to a situation in which no other elements are present in A other than B (i.e., a situation in which A consists solely and exclusively of B), and to a situation in which one or more other elements are present in entity A other than B (such as element C, elements C and D or even other elements).

[0010] Furthermore, as used hereinafter, the terms "preferably", "more preferably", "most preferably", "particularly", "more particularly", "specifically", "more specifically" or similar terms are used in conjunction with optional features without limiting further possibilities. Therefore, the features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way. As the skilled person will appreciate, the present invention can be carried out by using alternative features. Similarly, the features introduced by "in one embodiment of the present invention" or similar expressions are intended to be optional features without any limitation on other embodiments of the present invention, without any limitation on the scope of the present invention and without any limitation on the possibility of combining the features introduced in such a manner with other optional or non-optional features of the present invention.

[0011] The term "identifying a subject suffering from Alzheimer's dementia (AD)" is synonymous with "diagnosing a subject for Alzheimer's dementia (AD)", wherein "identifying" and "diagnosing" as used herein both refer to assessing whether a subject suffers from a Ka disease. Thus, the presence or absence of a disease in a subject can be diagnosed. Preferably, the term refers to determining or excluding the disease. As will be appreciated by those skilled in the art, such an assessment is generally not likely to be correct for 100% of the subjects examined, although it is preferred that it be correct for 100% of the subjects examined. However, the term requires that the subject of a statistically significant portion can be correctly assessed and thus diagnosed. Those skilled in the art can use various well-known statistical evaluation tools (e.g., determining confidence intervals, p-value determination, Student's t-test, Mann-Whitney test, etc.) to determine whether a portion is statistically significant without further ado. Details can be found, for example, in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983. Preferred confidence intervals are at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%. The p value is preferably 0.2 or lower, 0.1 or lower or 0.05 or lower.

[0012] The term "differentiation" and "diagnosis" include individual diagnosis of disease or its symptom and continuous monitoring of the patient. Monitoring (i.e. diagnosing the presence or absence of disease or its associated symptoms at different time points) includes monitoring of patients known to suffer from the disease and monitoring of subjects known to be at risk of developing the disease, such as monitoring of subjects with genetic susceptibility to the disease or subjects identified as being at risk based on the method identified above. In addition, monitoring can also be used to determine whether the patient is successfully treated or whether the symptoms of at least the disease can be improved over time by specific therapy. In addition, monitoring can be used for active patient management, including decision to be hospitalized, intensive care measures and / or other qualitative monitoring measures and quantitative monitoring measures.

[0013] The term "identifying a subject at risk of developing Alzheimer's dementia" refers to assessing the probability that a subject will develop Alzheimer's dementia within a specific time window (i.e., a prediction window). The term preferably relates to predicting whether there is an increased risk of Alzheimer's dementia compared to the average risk of developing Alzheimer's dementia in a population of subjects, rather than giving a precise probability of said risk.

[0014] Alzheimer's dementia (AD) (Morbus Alzheimer / Alzheimer's disease) is a neurodegenerative disease characterized by an increase in dementia. The methods known so far for determining whether a subject suffers from AD are the current diagnostic standards, preferably based on amyloid positron emission tomography and / or cerebrospinal fluid diagnosis and / or by cognitive testing. Biomarkers associated with AD are biomarkers of neurodegeneration known to the technician, such as, for example, Aβ-40, Aβ-42 or Aβ42 / 40 ratio in body fluids (blood, CSF), phosphorylated variants of Tau proteins (e.g., p-Tau181, p-Tau217, etc.), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), etc. The method for determining whether a subject suffers from AD involves determining cognitive ability in the subject by one or more tests known to the technician (such as, for example, ADAS-Cog, FCSRT, ADCS-iADL, QoL-AD, CDR, MMSE, etc.).

[0015] As used herein, the term "subject" relates to a multicellular animal, preferably to a vertebrate, more preferably to a mammal, more preferably to a human being.

[0016] A "body fluid sample" is a sample from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, preferably the body fluid sample is a blood sample.

[0017] The method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia is an in vitro method.

[0018] The term "determine amount" means the determination based on mass spectrometry (MS). Mass spectrometry as used herein encompasses all technologies allowing determination of the molecular weight (i.e., mass) or mass variables corresponding to a compound (i.e., metabolic analyte). More preferably, mass spectrometry as used herein relates to GC-MS, LC-MS, direct injection mass spectrometry, FT-ICR-MS, CE-MS, HPLC-MS, quadrupole mass spectrometry, any sequential coupling mass spectrometry such as MS-MS or MS-MS-MS, ICP-MS, Py-MS, TOF or any combination of methods using the above-mentioned techniques. How to apply these techniques is well known to those skilled in the art. In addition, suitable devices are commercially available. More preferably, mass spectrometry as used herein relates to LC-MS and / or GC-MS, i.e., relates to a mass spectrometry operably connected to a preceding chromatographic separation step. More preferably, mass spectrometry as used herein encompasses LC-MS / MS (liquid chromatography-mass spectrometry / mass spectrometry). Liquid chromatography as used herein refers to all techniques that allow separation of compounds (e.g., separation of at least two metabolic analytes to be determined according to the present invention) in a liquid phase or supercritical phase. Liquid chromatography is characterized in that the compounds in the mobile phase are passed through a stationary phase. When compounds pass through the stationary phase at different rates, they are separated over time because each individual compound has its specific retention time (i.e., the time required for the compound to pass through the system). Liquid chromatography as used herein also includes HPLC. Devices for liquid chromatography are commercially available, such as commercially available from Agilent Technologies, USA. Specific compounds and their specific masses and their amounts are determined based on the relevant peaks in the mass spectrum, respectively. Such peaks contain characteristic information (i.e., m / z information) of the compound and intensity values ​​related to the abundance (i.e., amount) of the compound in the sample.

[0019] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least one compound having a mass in grams / mole is selected from the group consisting of 110.0367, 232.004, 224.084, 254.1153, 189.9936 and 189.0096 (Group 2).

[0020] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least a compound having a mass of 110.0367 in grams / mole is determined in (a) and its determined amount is analyzed in (b).

[0021] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the amounts of at least two compounds, preferably at least three compounds, more preferably at least four compounds, more preferably at least five compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject in step (a) and analyzed in (b), wherein more preferably one of the at least two compounds, preferably one of the at least three compounds, more preferably one of the at least four compounds, more preferably one of the at least five compounds is a compound having a mass in grams / mole of 110.0367.

[0022] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the amounts of at least two compounds, preferably at least six compounds, more preferably at least seven compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject in step (a) and analyzed in (b), wherein more preferably one of the at least two compounds, more preferably one of the at least six compounds or one of the at least seven compounds is a compound having a mass in grams / mole of 110.0367.

[0023] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the amount of at least one other compound having a mass in grams / mole selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477 and 97.9769 (Group 3), preferably selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4) is additionally determined in step (a) in the first body fluid sample of the subject and analyzed additionally in (b).

[0024] In a first aspect, the present invention also relates to a method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0025] (a) determining the amount of at least two compounds having a mass in grams / mole selected from the group consisting of Group 3, preferably selected from the group consisting of Group 4, in a first body fluid sample of the subject;

[0026] (b) analyzing the determined amounts of the at least two compounds using a computer-implemented prediction algorithm capable of predicting AD in the subject based on the at least two compounds, thereby identifying the subject as having AD or at risk of developing Alzheimer's dementia if AD is predicted.

[0027] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the first body fluid sample is derived from the subject after administration of thiethylperazine or a pharmaceutically acceptable salt thereof to the subject, wherein the sample is preferably collected within 0.5 hours to 8 hours after TEP administration.

[0028] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the computer-implemented prediction algorithm uses a supervised machine learning algorithm that has been trained with a training data set comprising quantitative or qualitative data for the following compounds in body fluid samples from subjects known to have AD and subjects known not to have AD:

[0029] - at least one, preferably at least two, more preferably at least three, more preferably at least four, more preferably at least five compounds from group 1 or group 2, optionally in combination with at least one other compound from group 3; or optionally in combination with at least one other compound from group 4, or

[0030] - at least two, more preferably at least six, more preferably at least seven compounds from group 1 or group 2, optionally in combination with at least one further compound from group 3, or optionally in combination with at least one further compound from group 4; or

[0031] - at least two compounds from group 3, preferably from group 4.

[0032] As indicated above, according to current diagnostic criteria, it is preferably determined whether a subject has AD based on amyloid positron emission tomography and / or cerebrospinal fluid diagnosis and / or by cognitive testing.

[0033] The term "computer-implemented prediction algorithm" as used herein refers to a prediction algorithm automatically executed by a data processing device (such as a computer). The data processing device preferably includes tangibly embedded rules for automatically executing the prediction algorithm based on the measurement results obtained in the method of the present invention. The measurement results can preferably be stored in a database that can be permanently or temporarily linked to the data processor. In addition, the link can preferably be a direct link or a wireless link through a wire. The prediction algorithm as mentioned herein is an algorithm for determining parameters related to the possibility of a subject suffering from AD. The prediction algorithm as mentioned herein should generate the above parameters, and it can be further processed in order to establish a diagnosis according to the method of the present invention. Preferably, the (computer-implemented prediction) parameters can be determined as set forth elsewhere herein. In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the supervised machine learning algorithm establishes a classification algorithm selected from the group consisting of Logistic Regression, Stochastic Gradient Descent Classfier (SGD Classifier), Decision Tree Classfier, Random Tree Classfier, Extra Tree Classfier, AdaBoost Classfier, Multi-layer Perceptron Classfier, Gradient Boosting Classfier, Gaussian Naive Bayes, K Nearest Neighbor Classfier, C-Support Vector Classification, Quadratic Discriminant Analysis, and Linear Regression. In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the supervised machine learning algorithm establishes and / or applies a logistic regression model based on equation (I)

[0034] y = I + C1*F1 + C2*F2 +…+ C n *F n , (I)

[0035] where I is the intercept, and C n is the quality F n The coefficient of .

[0036] The prediction parameter implemented by the computer here is y. A positive y value indicates the possibility that the subject has or does not have AD, that is, a prediction of the corresponding condition. It will be understood that this is the case when training is based on the definition that AD diagnosis is a positive result, so the larger the absolute value means the greater the certainty of the prediction, that is, the larger the positive y value, the greater the possibility that the subject has AD, and the negative value of y with a higher absolute value indicates that the subject is more likely to not have AD. On the other hand, in the case of training based on the definition that AD diagnosis is a negative result, then the larger the negative y value, the greater the possibility that the subject has AD, and the positive value of y with a higher (absolute) value indicates that the subject is more likely to not have AD.

[0037] Each coefficient preferably has a value in the range as shown in Table 2 of the Experimental Part, wherein each range does not include zero - for each specific mass combination, see the relevant row called "Range" in Table 2. For example, for the combination of masses of 110.0367, 254.1153, 189.0096 and 224.084 (each in g / mol), the intercept I has a value in the range of -50 to +50 (excluding zero), and the coefficient C1 of the first characteristic (i.e. mass = 110.0367 / g / mol) is in the range of -150 to +150 (excluding zero), etc. Furthermore, it is even more preferred if the coefficients of the respective masses have ratios with each other in the ranges shown in the following Table A, more preferably as shown in the following Table B, more preferably as shown in the following Table C, wherein these ratios are more preferably applicable to the combination of masses from group 2, optionally in combination with masses from group 4:

[0038] Table A

[0039]

[0040] Table B

[0041]

[0042] Table C

[0043]

[0044] For each of Tables A, B, and C, the "lower half" refers to the portion below the diagonal line represented by the " / / " symbol, and the "upper half" refers to the portion above the line.

[0045] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 110.0367 g / mole, a compound having a mass of 189.0096 g / mole, a compound having a mass of 224.084 g / mole, and a compound having a mass of 254.1153 g / mole are determined in (a) and analyzed in (b).

[0046] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 189.993 g / mole, a compound having a mass of 224.084 g / mole, a compound having a mass of 232.004 g / mole, and a compound having a mass of 254.115 g / mole are determined in (a) and analyzed in (b).

[0047] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 175.0633 g / mol, a compound having a mass of 224.084 g / mol, a compound having a mass of 232.004 g / mol, a compound having a mass of 315.2409 g / mol, and a compound having a mass of 702.5682 g / mol are determined in (a) and analyzed in (b).

[0048] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 175.0633 g / mole, a compound having a mass of 208.0737 g / mole, and a compound having a mass of 254.1153 g / mole are determined in (a) and analyzed in (b).

[0049] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 110.0367 g / mole, a compound having a mass of 175.0633 g / mole, a compound having a mass of 224.084 g / mole, a compound having a mass of 254.1153 g / mole, and a compound having a mass of 315.2409 g / mole are determined in (a) and analyzed in (b).

[0050] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 175.0633 g / mole, a compound having a mass of 208.0737 g / mole, a compound having a mass of 315.2409 g / mole, and a compound having a mass of 702.5682 g / mole are determined in (a) and analyzed in (b).

[0051] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 110.0367 g / mole, a compound having a mass of 175.0633 g / mole, and a compound having a mass of 315.2409 g / mole are determined in (a) and analyzed in (b).

[0052] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 110.0367 g / mole, a compound having a mass of 208.0737 g / mole, a compound having a mass of 232.004 g / mole, and a compound having a mass of 315.2409 g / mole are determined in (a) and analyzed in (b).

[0053] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amount of the compound having a mass of 175.0633 g / mole and the compound having a mass of 208.0737 g / mole are determined in (a) and analyzed in (b).

[0054] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 110.0367 g / mole, a compound having a mass of 175.0633 g / mole, and a compound having a mass of 208.0737 g / mole are determined in (a) and analyzed in (b).

[0055] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amount of the compound having a mass of 208.0737 g / mole and the compound having a mass of 702.5682 g / mole are determined in (a) and analyzed in (b).

[0056] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 175.0633 g / mole, a compound having a mass of 208.0737 g / mole, and a compound having a mass of 315.2409 g / mole are determined in (a) and analyzed in (b).

[0057] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 110.0367 g / mol, a compound having a mass of 232.004 g / mol, a compound having a mass of 254.1153 g / mol, a compound having a mass of 189.9936 g / mol, a compound having a mass of 189.0096 g / mol, and a compound having a mass of 224.084 g / mol are determined in (a) and analyzed in (b).

[0058] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, at least the amounts of a compound having a mass of 110.0367 g / mol, a compound having a mass of 110.0367 g / mol, a compound having a mass of 175.0633 g / mol, a compound having a mass of 702.5682 g / mol, a compound having a mass of 208.0737 g / mol, a compound having a mass of 315.2409 g / mol, a compound having a mass of 232.004 g / mol, and a compound having a mass of 254.1153 g / mol are determined in (a) and analyzed in (b).

[0059] Aspect 2 - for the identification of patients with or at risk of developing Alzheimer's dementia (AD) Subjects at risk approach (variation-based modeling)

[0060] In a second aspect, the present invention relates to a method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0061] (a) determining in a first bodily fluid sample of the subject an amount of at least one compound having a mass in grams per mole selected from the group consisting of: 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.345, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.0 452, 212.0536, 234.1832, 236.1049, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 319.2486, 331.2545, 332.1372, 334.2146, 339.3135, 346.1528, 350.0956, 366.0912, 371.8758, 440.2751, 538.1752, 540.2563 and 782.5638 (Group 1);

[0062] (b) determining the amount of at least one compound as in (a) in a second bodily fluid sample of the subject;

[0063] (c) determining a change in the amount of at least one compound determined according to (a) compared to the corresponding amount of at least one compound determined according to (b);

[0064] (d) analyzing the changes determined in (c) using a computer-implemented prediction algorithm capable of predicting AD in a subject based on the at least one compound, thereby identifying a subject having AD or at risk of developing Alzheimer's dementia if AD is predicted;

[0065] The first body fluid sample is obtained before administering thiethylperazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0066] The definitions indicated above in the section relating to the first aspect also apply here in the section relating to the second aspect of the invention.

[0067] Thiethylperazine (IUPAC: 2-(ethylsulfanyl)-10-[3-(4-methylpiperazin-1-yl)propyl]-10H-phenothiazine, CAS: 1420-55-9, TEP) has been shown to effectively export amyloid β (Aβ) from and through the endothelial cells of the blood-brain barrier to the periphery in an Alzheimer's disease (AD) mouse model. It has also been demonstrated that pharmacological activation of ABCC1 can reduce amyloid plaque deposition in the brain. As used herein, the term "pharmaceutically acceptable" relates to salts that are pharmaceutically acceptable in the sense that they are not harmful to the recipient thereof and are preferably compatible with other optional ingredients of its formulation. Preferably, a pharmaceutically acceptable salt is a salt of thiethylperazine that causes no more than moderate adverse drug reactions, preferably no more than mild adverse drug reactions. As used herein, the term "mild" adverse reactions relate to adverse reactions that do not require medical intervention, such as rash, headache, digestive disturbances, fatigue, etc.; "moderate" adverse reactions are adverse reactions that require medical intervention but are not potentially life-threatening. Preferably, the pharmaceutically acceptable salt comprises one or more anions selected from the group consisting of sulfate, pyrosulfate, hydrogensulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate , benzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, almondate, adipate, alginate, mucate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, hexanoate, 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, picrate, pivalate, salicylate, thiocyanate, toluenesulfonate, arginate, and undecanoate.More preferably, the pharmaceutically acceptable salt comprises one or more anions selected from the group consisting of chloride, sulfate, methanesulfonate, benzenesulfonate, toluenesulfonate, fumarate, malonate, malate, maleate, succinate, lactate, glycolate, citrate, aspartate and mandelate, preferably malate and / or maleate, more preferably maleate.

[0068] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least one compound having a mass in grams / mole (the amounts of which are determined in (a) and (b), the changes of which are determined in (c) and analyzed in (d)) is selected from the group consisting of 110.0367, 232.004, 224.084, 254.1153, 189.9936 and 189.0096 (Group 2).

[0069] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least one compound having a mass in grams / mole (the amounts of which are determined in (a) and (b), the changes determined in (c) and analyzed in (d)) is at least a compound having a mass in grams / mole of 110.0367.

[0070] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, the amounts of at least two compounds, preferably at least three compounds, more preferably at least four compounds, more preferably at least five compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in (a) and (b), the change compared is determined in (c), and the analysis is performed in (d), wherein more preferably one of the at least two compounds, preferably one of the at least three compounds, more preferably one of the at least four compounds, more preferably one of the at least five compounds is a compound having a mass in grams per mole of 110.0367.

[0071] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, the amounts of at least two compounds, preferably at least six compounds or at least seven compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in (a) and (b), the change compared is determined in (c), and the analysis is performed in (d), wherein more preferably one of the at least two compounds, more preferably one of the at least six compounds or one of the at least seven compounds is a compound having a mass in grams per mole of 110.0367.

[0072] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, the amount of at least one other compound having a mass in grams / mole selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477 and 97.9769 (Group 3), preferably selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4) is additionally determined in (a) and (b), the change compared to is determined in (c), and analysis is performed in (d).

[0073] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, the method comprises:

[0074] (a) determining the amount of at least two compounds having a mass in grams / mole selected from the group consisting of Group 3, preferably selected from the group consisting of Group 4, in a first body fluid sample of the subject;

[0075] (b) determining the amounts of at least two of the same compounds as in (a) in a second bodily fluid sample from the subject;

[0076] (c) determining a change in the amounts of at least two compounds determined according to (a) compared to the corresponding amounts of at least two compounds determined according to (b);

[0077] (d) analyzing the changes determined in (c) using a computer-implemented prediction algorithm capable of predicting AD in a subject based on the at least one compound, thereby identifying the subject as having AD or at risk of developing Alzheimer's dementia if AD is predicted.

[0078] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of a compound having a mass of 110.0367 g / mol, a compound having a mass of 189.0096 g / mol, a compound having a mass of 224.084 g / mol, and a compound having a mass of 254.1153 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and analysis is performed in (d).

[0079] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of a compound having a mass of 189.993 g / mol, a compound having a mass of 224.084 g / mol, a compound having a mass of 232.004 g / mol, and a compound having a mass of 254.115 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and analysis is performed in (d).

[0080] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of a compound having a mass of 175.0633 g / mol, a compound having a mass of 224.084 g / mol, a compound having a mass of 232.004 g / mol, a compound having a mass of 315.2409 g / mol, and a compound having a mass of 702.5682 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and analysis is performed in (d).

[0081] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of the compound having a mass of 175.0633 g / mol, the compound having a mass of 208.0737 g / mol, and the compound having a mass of 254.1153 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0082] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of a compound having a mass of 110.0367 g / mol, a compound having a mass of 175.0633 g / mol, a compound having a mass of 224.084 g / mol, a compound having a mass of 254.1153 g / mol, and a compound having a mass of 315.2409 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and analysis is performed in (d).

[0083] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of a compound having a mass of 175.0633 g / mol, a compound having a mass of 208.0737 g / mol, a compound having a mass of 315.2409 g / mol, and a compound having a mass of 702.5682 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and analysis is performed in (d).

[0084] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of the compound having a mass of 110.0367 g / mol, the compound having a mass of 175.0633 g / mol, and the compound having a mass of 315.2409 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0085] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of a compound having a mass of 110.0367 g / mol, a compound having a mass of 208.0737 g / mol, a compound having a mass of 232.004 g / mol, and a compound having a mass of 315.2409 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and analysis is performed in (d).

[0086] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amount of the compound with a mass of 175.0633 g / mole and the amount of the compound with a mass of 208.0737 g / mole are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0087] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of the compound having a mass of 110.0367 g / mol, the compound having a mass of 175.0633 g / mol, and the compound having a mass of 208.0737 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0088] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amount of the compound with a mass of 208.0737 g / mole and the amount of the compound with a mass of 702.5682 g / mole are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0089] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of the compound having a mass of 175.0633 g / mol, the compound having a mass of 208.0737 g / mol, and the compound having a mass of 315.2409 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0090] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of a compound having a mass of 110.0367 g / mol, a compound having a mass of 232.004 g / mol, a compound having a mass of 254.1153 g / mol, a compound having a mass of 189.9936 g / mol, a compound having a mass of 189.0096 g / mol, and a compound having a mass of 224.084 g / mol are determined in (a) and (b), the change compared to the above is determined in (c), and analysis is performed in (d).

[0091] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the second aspect, at least the amounts of a compound having a mass of 110.0367 g / mol, a compound having a mass of 110.0367 g / mol, a compound having a mass of 175.0633 g / mol, a compound having a mass of 702.5682 g / mol, a compound having a mass of 208.0737 g / mol, a compound having a mass of 315.2409 g / mol, a compound having a mass of 232.004 g / mol, and a compound having a mass of 254.1153 g / mol are determined in (a) and (b), the change compared to the above is determined in (c), and analysis is performed in (d).

[0092] The amount determination in any of steps (a) and / or (b) is performed by mass spectrometry (MS), preferably by tandem mass spectrometry (MS / MS), more preferably by tandem mass spectrometry (LC-MS / MS) combined with a preceding liquid chromatography; further details can be found in the section relating to the first aspect of the invention. The method is an in vitro method. As used herein, the term "subject" relates to a multicellular animal, preferably a vertebrate, more preferably a mammal, more preferably a human. The body fluid sample is selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, preferably the body fluid sample is a blood sample; and the first body fluid sample and the second body fluid sample are independently selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, respectively, wherein preferably, the first body fluid sample and the second body fluid sample are samples of the same type and are both selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, wherein more preferably, the first body fluid sample and the second body fluid sample are each blood samples (first blood sample and second blood sample).

[0093] Aspect 3 - for the identification of patients with or at risk of developing Alzheimer's dementia (AD) Methods of subjects at risk (comparison of the amount before and after TEP administration)

[0094] In a third aspect, the present invention relates to a method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0095] (a) determining in a first bodily fluid sample of the subject an amount of at least one compound having a mass in grams per mole selected from the group consisting of: 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.345, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.0 452, 212.0536, 234.1832, 236.1049, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 319.2486, 331.2545, 332.1372, 334.2146, 339.3135, 346.1528, 350.0956, 366.0912, 371.8758, 440.2751, 538.1752, 540.2563 and 782.5638 (Group 1);

[0096] (b) determining the amount of at least one compound as in (a) in a second bodily fluid sample of the subject;

[0097] (c) comparing the amount of the at least one compound determined according to (a) to a corresponding amount of the at least one compound determined according to (b), wherein a change in the amount of the at least one compound according to (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia;

[0098] The first body fluid sample is obtained before administering thiethylperazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0099] The definitions indicated above in the section relating to the first aspect also apply here to the section relating to the third aspect of the invention. Thiethylperazine (IUPAC: 2-(ethylsulfanyl)-10-[3-(4-methylpiperazin-1-yl)propyl]-10H-phenothiazine, CAS: 1420-55-9, TEP) and its pharmaceutically acceptable salts are also as defined above in the section relating to the second aspect.

[0100] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least one compound having a mass in grams / mole is selected from the group consisting of 110.0367, 232.004, 224.084, 254.1153, 189.9936 and 189.0096 (Group 2).

[0101] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amount of the compound having a mass of 110.0367 g / mole is determined in (a) and (b) and compared in (c).

[0102] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, the amounts of at least two compounds, preferably at least three compounds, more preferably at least four compounds, more preferably at least five compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change in the amount of each of the at least two compounds, preferably each of the at least three compounds, more preferably each of the at least four compounds, more preferably each of the at least five compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia, wherein more preferably one of the at least two compounds, preferably one of the at least three compounds, more preferably one of the at least four compounds, more preferably one of the at least five compounds is a compound with a mass of 110.0367 grams per mole.

[0103] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, the amounts of at least two compounds, preferably at least six compounds or at least seven compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change in the amount of each of the at least two compounds, preferably each of the at least six compounds, more preferably each of the at least seven compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia, wherein more preferably one of the at least two compounds, more preferably one of the at least six compounds or one of the at least seven compounds is a compound with a mass of 110.0367 grams per mole.

[0104] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, the amount of at least one other compound is additionally determined in the first body fluid sample of the subject in steps (a) and (b), the at least one other compound having a nucleotide sequence selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477 and 97.9769 (Group 3), More preferably, the mass in grams / mole is selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4) and compared in (c), wherein the change in the amount of at least one compound according to (b) compared to the amount determined in (a) and the change in the amount of at least one other compound according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0105] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, the method comprises:

[0106] (a) determining the amount of at least two compounds having a mass in grams / mole selected from the group consisting of Group 3, preferably Group 4, in a first body fluid sample of the subject;

[0107] (b) determining the amounts of at least two of the same compounds as in (a) in a second bodily fluid sample from the subject;

[0108] (c) comparing the amounts of the at least two compounds determined according to (a) with the corresponding amounts of the at least two compounds determined according to (b), wherein a change in the amounts of the at least two compounds according to (b) compared to the amounts determined in (a) is indicative of Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia;

[0109] The first body fluid sample is obtained before administering thiethylperazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0110] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 189.0096 g / mole, a compound with a mass of 224.084 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0111] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 189.993 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 254.115 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0112] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 232.004 g / mole, a compound with a mass of 315.2409 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0113] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 12.5% ​​in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0114] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 254.1153 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0115] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 315.2409 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 12.5% ​​in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0116] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 2% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0117] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0118] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amount of a compound with a mass of 175.0633 g / mole and a compound with a mass of 208.0737 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 12.5% ​​in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia.

[0119] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole and a compound with a mass of 208.0737 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0120] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amount of a compound with a mass of 208.0737 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0121] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 40% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0122] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 232.004 g / mole, a compound with a mass of 254.1153 g / mole, a compound with a mass of 189.9936 g / mole, a compound with a mass of 189.0096 g / mole and a compound with a mass of 224.084 g / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0123] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia of the third aspect, at least the amounts of a compound with a mass of 110.0367 g / mol, a compound with a mass of 110.0367 g / mol, a compound with a mass of 175.0633 g / mol, a compound with a mass of 702.5682 g / mol, a compound with a mass of 208.0737 g / mol, a compound with a mass of 315.2409 g / mol, a compound with a mass of 232.004 g / mol and a compound with a mass of 254.1153 g / mol are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), wherein a change of at least 2% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia.

[0124] The amount determination in any of steps (a) and / or (b) is performed by mass spectrometry (MS), preferably by tandem mass spectrometry (MS / MS), more preferably by tandem mass spectrometry (LC-MS / MS) combined with a preceding liquid chromatography, further details of which can be found in the section relating to the first aspect of the invention. The method is an in vitro method. As used herein, the term "subject" relates to a multicellular animal, preferably a vertebrate, more preferably a mammal, more preferably a human. The body fluid sample is selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, preferably the body fluid sample is a blood sample; and the first body fluid sample and the second body fluid sample are independently selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, respectively, wherein preferably, the first body fluid sample and the second body fluid sample are samples of the same type and are both selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, wherein more preferably, the first body fluid sample and the second body fluid sample are each blood samples (first blood sample and second blood sample).

[0125] Aspect 4 - Method for identifying a subject with Alzheimer's dementia (AD) (the amount of TEP after administration) Comparison with reference value)

[0126] A fourth aspect of the present invention relates to a method for identifying a subject suffering from Alzheimer's dementia (AD), the method comprising:

[0127] (a) determining in a bodily fluid sample of the subject an amount of at least one compound having a mass in grams per mole selected from the group consisting of: 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.345, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.04 52, 212.0536, 234.1832, 236.1049, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 319.2486, 331.2545, 332.1372, 334.2146, 339.3135, 346.1528, 350.0956, 366.0912, 371.8758, 440.2751, 538.1752, 540.2563 and 782.5638 (Group 1);

[0128] (b) comparing the amount of the at least one compound determined according to (a) with an average amount in healthy subjects, wherein a change in the amount of the at least one compound according to (a) compared to the average amount in healthy subjects, preferably a change of at least 3% based on the average amount in healthy subjects as 100%, is indicative of Alzheimer's dementia in the subject or that the subject is at risk of developing Alzheimer's dementia;

[0129] The body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0130] The definitions given in the section relating to the first aspect and the explanations given in the second and third sections relating to thiethylperazine (TEP) and pharmaceutically acceptable salts thereof also apply here to the section relating to the fourth aspect of the present invention.

[0131] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least one compound having a mass in grams / mole is selected from the group consisting of 110.0367, 232.004, 224.084, 254.1153, 189.9936 and 189.0096 (Group 2).

[0132] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amount of the compound having a mass of 110.0367 in grams / mole is determined in (a) and compared in (b).

[0133] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, the amounts of at least two compounds, preferably at least three compounds, more preferably at least four compounds, more preferably at least five compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change in the amount of each of the at least two compounds, preferably each of the at least three compounds, more preferably each of the at least four compounds, more preferably each of the at least five compounds indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia, wherein more preferably one of the at least two compounds, preferably one of the at least three compounds, more preferably one of the at least four compounds, more preferably one of the at least five compounds is a compound having a mass in grams per mole of 110.0367.

[0134] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, the amounts of at least two compounds, preferably at least six compounds, more preferably at least seven compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change in the amount of each of the at least two compounds, preferably each of the at least six compounds, more preferably each of the at least seven compounds indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia, wherein more preferably one of the at least two compounds, more preferably one of the at least six compounds or one of the at least seven compounds is a compound with a mass in grams / mole of 110.0367.

[0135] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, the amount of at least one other compound is determined in a first body fluid sample of the subject in step (a), the at least one other compound having a mass in grams / mole selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477 and 97.9769 (Group 3), more preferably selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4), and is compared in (b), wherein a change in the amount of each of the at least one compound compared to the average amount in healthy subjects, preferably a change of at least 3% based on the average amount in healthy subjects as 100%, indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia.

[0136] A fourth aspect of the present invention also relates to a method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0137] (a) determining the amount of at least two compounds having a mass in grams / mole selected from the group consisting of Group 3, preferably selected from the group consisting of Group 4, in a body fluid sample of a subject;

[0138] (b) comparing the amounts of the at least two compounds determined according to (a) with the average amounts in healthy subjects, wherein a change in the amounts of the at least two compounds according to (a) compared to the average amounts in healthy subjects, preferably a change of at least 3% based on the average amounts in healthy subjects as 100%, is indicative of Alzheimer's dementia in the subject or of the subject being at risk of developing Alzheimer's dementia;

[0139] The body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0140] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 189.0096 g / mole, a compound with a mass of 224.084 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0141] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 189.993 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 254.115 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0142] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 232.004 g / mole, a compound with a mass of 315.2409 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0143] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia.

[0144] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 254.1153 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0145] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 315.2409 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0146] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia.

[0147] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0148] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 175.0633 g / mole and a compound with a mass of 208.0737 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia.

[0149] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole and a compound with a mass of 208.0737 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0150] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 208.0737 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 12% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia.

[0151] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia.

[0152] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 232.004 g / mole, a compound with a mass of 254.1153 g / mole, a compound with a mass of 189.9936 g / mole, a compound with a mass of 189.0096 g / mole and a compound with a mass of 224.084 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0153] In some preferred embodiments of the method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole, a compound with a mass of 702.5682 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 315.2409 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0154] In some preferred embodiments of the method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia relating to the fourth aspect, the average amount for healthy subjects is a reference value for healthy subjects from the literature, or a reference value previously determined from healthy subjects, or a reference value from a body fluid sample of a subject before TEP administration.

[0155] The amount determination in any of steps (a) and / or (b) is performed by mass spectrometry (MS), preferably by tandem mass spectrometry (MS / MS), more preferably by tandem mass spectrometry (LC-MS / MS) combined with a preceding liquid chromatography, further details of which can be found in the section relating to the first aspect of the invention. The method is an in vitro method. As used herein, the term "subject" relates to a multicellular animal, preferably a vertebrate, more preferably a mammal, more preferably a human. The body fluid sample is selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, preferably the body fluid sample is a blood sample; and the first body fluid sample and the second body fluid sample are independently selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, respectively, wherein preferably, the first body fluid sample and the second body fluid sample are samples of the same type and are both selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, wherein more preferably, the first body fluid sample and the second body fluid sample are each blood samples (first blood sample and second blood sample).

[0156] Aspect 5 - Second diagnostic use

[0157] The fifth aspect of the invention relates to at least one compound having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 or as defined in any of the preferred embodiments described in the previous parts relating to the first, second, third or fourth aspect of the invention, and optionally in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3, preferably selected from the group consisting of Group 4, for use in diagnosing AD in a subject or for determining the risk of a subject developing AD.

[0158] Group 1, Group 2, Group 3 and Group 4 are as defined above in the section relating to the first, second, third or fourth aspect of the invention.

[0159] In some preferred embodiments of at least one compound used according to the fifth aspect, at least two compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 described above in the section relating to the first, second, third or fourth aspect of the invention are used, preferably at least three compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 as defined in any of the preferred embodiments described above in the section relating to the first, second, third or fourth aspect of the invention, more preferably at least four compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 as defined in any of the preferred embodiments described above in the section relating to the first, second, third or fourth aspect of the invention; more preferably at least five compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 as defined in any of the preferred embodiments described above in the section relating to the first, second, third or fourth aspect of the invention, each optionally combined with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4.

[0160] In some preferred embodiments of at least one compound used according to the fifth aspect, at least two compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 as defined in any of the preferred embodiments described above in the parts relating to the first, second, third or fourth aspects of the invention are used, preferably at least six compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 as defined in any of the preferred embodiments described above in the parts relating to the first, second, third or fourth aspects of the invention, and more preferably at least seven compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 as defined in any of the preferred embodiments described above in the parts relating to the first, second, third or fourth aspects of the invention; each optionally combined with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4.

[0161] In some preferred embodiments of the at least one compound for use according to the fifth aspect, at least two compounds having masses in grams / mole selected from the group consisting of Group 3 or Group 4 are used to diagnose AD in a subject or to determine the risk of a subject developing AD.

[0162] Second diagnostic use (alternative wording)

[0163] The fifth aspect of the present invention also relates to the use of a sample from a subject having at least one compound with a mass in grams / mole selected from the group consisting of Group 1 or Group 2 as defined in any of the preferred embodiments described above in the parts relating to the first, second, third or fourth aspects of the present invention, and optionally in combination with at least one compound with a mass in grams / mole selected from the group consisting of Group 3 or Group 4 for diagnosing AD in the subject or for determining the risk of the subject developing AD.

[0164] Group 1, Group 2, Group 3 and Group 4 are as defined above in the section relating to the first, second, third or fourth aspect of the invention.

[0165] In some preferred embodiments of the use according to the fifth aspect, a sample from a subject having a mass in grams / mole of at least two, preferably at least three, more preferably at least four, more preferably at least five compounds selected from the group consisting of Group 1 or Group 2 as defined in any of the preferred embodiments described above in the part relating to the first, second, third or fourth aspect of the invention, and optionally in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4 is used to diagnose AD in the subject or to determine the risk of the subject developing AD.

[0166] In some preferred embodiments of the use according to the fifth aspect, a sample from a subject having a mass in grams / mole of at least two, preferably at least six, more preferably at least seven compounds selected from the group consisting of Group 1 or Group 2 as defined in any of the preferred embodiments described above in the part relating to the first, second, third or fourth aspect of the invention, and optionally in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4 is used to diagnose AD in the subject or to determine the risk of the subject developing AD.

[0167] In some preferred embodiments of the use according to the fifth aspect, at least two compounds having a mass in grams / mole selected from the group consisting of Group 3 or Group 4 in a sample of a subject are used to diagnose AD in the subject or to determine the risk of the subject developing AD.

[0168] Aspect 6 - Devices

[0169] A sixth aspect of the invention relates to a device suitable for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the device comprising:

[0170] (a) an analytical unit capable of determining the amount of at least one compound having a mass in grams / mole selected from the group consisting of Group 1 in a first body fluid sample of a subject;

[0171] (b) a data processor for analyzing the determined amount of at least one compound using a prediction algorithm implemented in the data processor, the prediction algorithm being capable of predicting AD in the subject based on the at least two compounds, thereby identifying a subject having AD if AD is predicted, or identifying a subject at risk of developing Alzheimer's dementia if AD is predicted.

[0172] Preferred embodiments of the device, in particular those involving compounds having specific masses in g / mol and specific groups thereof, such as Group 2, Group 3 and Group 4, are as described above in the sections relating to the first, second, third or fourth aspect of the invention. In addition, the definitions indicated above in these sections also apply here to the sections relating to the device.

[0173] Aspect 7 - Kit

[0174] In a seventh aspect, the present invention relates to a kit for identifying subjects suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the kit comprising a reference sample having a mass in grams / mole of at least one compound selected from the group consisting of Group 1 or Group 2, optionally a reference sample having a mass in grams / mole of at least one compound selected from the group consisting of Group 3, or optionally a reference sample having a mass in grams / mole of at least one compound selected from the group consisting of Group 4, and optionally one or more reagents for sample preparation and / or extraction.

[0175] Preferred embodiments of the device, in particular those involving compounds having specific masses in g / mol and specific groups thereof, such as Group 2, Group 3 and Group 4, are as described above in the sections relating to the first, second, third or fourth aspect of the invention. In addition, the definitions indicated above in these sections also apply here to the sections relating to the device.

[0176] The present invention is further illustrated by the following embodiments and combinations of embodiments (as indicated by respective dependencies and back references). In particular, it should be noted that in each case where the scope of an embodiment is mentioned, for example in the context of a term such as "a method according to any one of embodiments 1 to 4", each embodiment within the scope is intended to be explicitly disclosed to the skilled person, i.e. the wording of the term should be understood by the skilled person as being synonymous with "a method according to any one of embodiments 1, 2, 3 and 4".

[0177] 1. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0178] (a) determining in a first bodily fluid sample of the subject an amount of at least one compound having a mass in grams per mole selected from the group consisting of: 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.345, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.0 452, 212.0536, 234.1832, 236.1049, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 319.2486, 331.2545, 332.1372, 334.2146, 339.3135, 346.1528, 350.0956, 366.0912, 371.8758, 440.2751, 538.1752, 540.2563 and 782.5638 (Group 1);

[0179] (b) analyzing the determined amount of the at least one compound using a computer-implemented prediction algorithm capable of predicting AD in the subject based on the at least one compound, thereby identifying the subject as having AD or at risk of developing Alzheimer's dementia if AD is predicted,

[0180] Preferably, the first body fluid sample is derived from the subject after thioethylperazine (TEP) or a pharmaceutically acceptable salt thereof is administered to the subject, wherein the sample is preferably collected within 0.5 to 8 hours after the administration of TEP.

[0181] 2. The method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to embodiment 1, wherein at least one compound having a mass in grams / mole is selected from the group consisting of 110.0367, 232.004, 224.084, 254.1153, 189.9936 and 189.0096 (Group 2).

[0182] 3. The method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to embodiment 1 or 2, wherein at least a compound having a mass of 110.0367 in grams / mole is determined in (a) and its determined amount is analyzed in (b).

[0183] 4. A method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 1 to 3, wherein in step (a) the amounts of at least two compounds, preferably at least three compounds, more preferably at least four compounds, more preferably at least five compounds having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject, and analyzed in (b), wherein more preferably one of the at least two compounds, preferably one of the at least three compounds, more preferably one of the at least four compounds, more preferably one of the at least five compounds is a compound having a mass in grams / mole of 110.0367.

[0184] 5. A method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 1 to 4, wherein in step (a) the amounts of at least two compounds, preferably at least six compounds, more preferably at least seven compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject and analyzed in (b), wherein more preferably one of the at least two compounds, more preferably one of the at least six compounds or one of the at least seven compounds is a compound having a mass in grams per mole of 110.0367.

[0185] 6. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia according to any one of embodiments 1 to 4, wherein in step (a) the amount of at least one other compound having a mass in grams / mole selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477 and 97.9769 (Group 3), preferably selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4) is additionally determined in the first body fluid sample of the subject and analyzed additionally in (b).

[0186] 7. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0187] (a) determining the amount of at least two compounds having a mass in grams / mole selected from the group consisting of Group 3, preferably selected from the group consisting of Group 4, in a first body fluid sample of the subject;

[0188] (b) analyzing the determined amounts of the at least two compounds using a computer-implemented prediction algorithm capable of predicting AD in the subject based on the at least two compounds, thereby identifying the subject as having AD or at risk of developing Alzheimer's dementia if AD is predicted.

[0189] 8. The method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 1 to 7, wherein the computer-implemented prediction algorithm uses a supervised machine learning algorithm that has been trained with a training data set comprising quantitative or qualitative data of the following compounds in body fluid samples from subjects known to have AD and subjects known not to have AD:

[0190] - at least one, preferably at least two, more preferably at least three, more preferably at least four, more preferably at least five compounds from group 1 or group 2, optionally in combination with at least one other compound from group 3; or optionally in combination with at least one other compound from group 4, or

[0191] - at least two, more preferably at least six, more preferably at least seven compounds from group 1 or group 2, optionally in combination with at least one further compound from group 3, or optionally in combination with at least one further compound from group 4; or

[0192] - at least two compounds from group 3, preferably from group 4.

[0193] 9. A method according to embodiment 8, wherein the supervised machine learning algorithm establishes a classification algorithm selected from the group consisting of: logistic regression, stochastic gradient descent classifier (SGD classifier), decision tree classifier, random tree classifier, extreme tree classifier, AdaBoost classifier, multilayer perceptron classifier, gradient boosting classifier, Gaussian naive Bayes, K nearest neighbor classifier, C-support vector classification, quadratic discriminant analysis and linear regression.

[0194] 10. A method according to embodiment 9, wherein the supervised machine learning algorithm establishes and / or applies a logistic regression model based on equation (I)

[0195] y = I + C1*F1 + C2*F2 +…+ C n *F n , (I)

[0196] where I is the intercept, and C n is the quality F n The coefficient of .

[0197] 12. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 189.0096 g / mol, the compound with a mass of 224.084 g / mol and the compound with a mass of 254.1153 g / mol is determined in (a) and analyzed in (b).

[0198] 13. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 189.993 g / mol, the compound with a mass of 224.084 g / mol, the compound with a mass of 232.004 g / mol and the compound with a mass of 254.115 g / mol is determined in (a) and analyzed in (b).

[0199] 14. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 175.0633 g / mol, the compound with a mass of 224.084 g / mol, the compound with a mass of 232.004 g / mol, the compound with a mass of 315.2409 g / mol and the compound with a mass of 702.5682 g / mol is determined in (a) and analyzed in (b).

[0200] 15. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 175.0633 g / mol, the compound with a mass of 208.0737 g / mol and the compound with a mass of 254.1153 g / mol is determined in (a) and analyzed in (b).

[0201] 16. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 175.0633 g / mol, the compound with a mass of 224.084 g / mol, the compound with a mass of 254.1153 g / mol and the compound with a mass of 315.2409 g / mol is determined in (a) and analyzed in (b).

[0202] 17. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 175.0633 g / mol, the compound with a mass of 208.0737 g / mol, the compound with a mass of 315.2409 g / mol and the compound with a mass of 702.5682 g / mol is determined in (a) and analyzed in (b).

[0203] 18. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 175.0633 g / mol and the compound with a mass of 315.2409 g / mol is determined in (a) and analyzed in (b).

[0204] 19. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 208.0737 g / mol, the compound with a mass of 232.004 g / mol and the compound with a mass of 315.2409 g / mol is determined in (a) and analyzed in (b).

[0205] 20. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 175.0633 g / mol and the compound with a mass of 208.0737 g / mol is determined in (a) and analyzed in (b).

[0206] 21. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 175.0633 g / mol and the compound with a mass of 208.0737 g / mol is determined in (a) and analyzed in (b).

[0207] 22. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 208.0737 g / mol and the compound with a mass of 702.5682 g / mol is determined in (a) and analyzed in (b).

[0208] 23. The method according to any one of embodiments 1 to 10, wherein at least the amount of the compound with a mass of 175.0633 g / mol, the compound with a mass of 208.0737 g / mol and the compound with a mass of 315.2409 g / mol is determined in (a) and analyzed in (b).

[0209] 24. The method according to any one of embodiments 1 to 10, wherein at least the amounts of the compound with a mass of 110.0367 g / mol, the compound with a mass of 232.004 g / mol, the compound with a mass of 254.1153 g / mol, the compound with a mass of 189.9936 g / mol, the compound with a mass of 189.0096 g / mol and the compound with a mass of 224.084 g / mol are determined in (a) and analyzed in (b).

[0210] 25. The method according to any one of embodiments 1 to 10, wherein at least the amounts of the compound with a mass of 110.0367 g / mol, the compound with a mass of 110.0367 g / mol, the compound with a mass of 175.0633 g / mol, the compound with a mass of 702.5682 g / mol, the compound with a mass of 208.0737 g / mol, the compound with a mass of 315.2409 g / mol, the compound with a mass of 232.004 g / mol and the compound with a mass of 254.1153 g / mol are determined in (a) and analyzed in (b).

[0211] 25. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0212] (a) determining in a first bodily fluid sample of the subject an amount of at least one compound having a mass in grams per mole selected from the group consisting of: 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.345, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.0 452, 212.0536, 234.1832, 236.1049, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 319.2486, 331.2545, 332.1372, 334.2146, 339.3135, 346.1528, 350.0956, 366.0912, 371.8758, 440.2751, 538.1752, 540.2563 and 782.5638 (Group 1);

[0213] (b) determining the amount of at least one compound as in (a) in a second bodily fluid sample of the subject;

[0214] (c) determining a change in the amount of at least one compound determined according to (a) compared to the corresponding amount of at least one compound determined according to (b);

[0215] (d) analyzing the changes determined in (c) using a computer-implemented prediction algorithm capable of predicting AD in a subject based on the at least one compound, thereby identifying a subject having AD or at risk of developing Alzheimer's dementia if AD is predicted;

[0216] The first body fluid sample is obtained before administering thiethylperazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0217] 26. The method according to embodiment 25, wherein at least one compound having a mass in grams per mole (the amounts of which are determined in (a) and (b), the changes of which are determined in (c), and analyzed in (c)) is selected from the group consisting of 110.0367, 232.004, 224.084, 254.1153, 189.9936, and 189.0096 (Group 2).

[0218] 27. The method according to embodiment 25 or 26, wherein at least one compound having a mass in g / mol (whose amount is determined in (a) and (b), the change is determined in (c) and analyzed in (c)) is at least a compound having a mass in g / mol of 110.0367.

[0219] 28. The method according to any one of embodiments 25 to 27, wherein the amounts of at least two compounds, preferably at least three compounds, more preferably at least four compounds, more preferably at least five compounds having a mass in g / mol selected from the group consisting of Group 1 or Group 2 are determined in (a) and (b), the change in comparison is determined in (c), and the analysis is performed in (d), wherein more preferably one of the at least two compounds, preferably one of the at least three compounds, more preferably one of the at least four compounds, more preferably one of the at least five compounds is a compound having a mass in g / mol of 110.0367.

[0220] 29. The method according to any one of embodiments 25 to 28, wherein the amounts of at least two compounds, preferably at least six compounds or at least seven compounds having a mass in g / mol selected from the group consisting of Group 1 or Group 2 are determined in (a) and (b), the change in comparison is determined in (c), and the analysis is performed in (d), wherein more preferably one of the at least two compounds, more preferably one of the at least six compounds or one of the at least seven compounds is a compound having a mass in g / mol of 110.0367.

[0221] 30. The method according to any one of embodiments 25 to 29, wherein the amount of at least one other compound having a mass in grams per mole selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477 and 97.9769 (Group 3), preferably selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4) is additionally determined in (a) and (b), the change compared to is determined in (c), and the analysis is performed in (d).

[0222] 31. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0223] (a) determining the amount of at least two compounds having a mass in grams / mole selected from the group consisting of Group 3, preferably selected from the group consisting of Group 4, in a first body fluid sample of the subject;

[0224] (b) determining the amounts of at least two of the same compounds as in (a) in a second bodily fluid sample from the subject;

[0225] (c) determining a change in the amounts of at least two compounds determined according to (a) compared to the corresponding amounts of at least two compounds determined according to (b);

[0226] (d) analyzing the changes determined in (c) using a computer-implemented prediction algorithm capable of predicting AD in a subject based on the at least one compound, thereby identifying the subject as having AD or at risk of developing Alzheimer's dementia if AD is predicted.

[0227] 32. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 189.0096 g / mol, the compound with a mass of 224.084 g / mol and the compound with a mass of 254.1153 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0228] 33. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 189.993 g / mol, the compound with a mass of 224.084 g / mol, the compound with a mass of 232.004 g / mol and the compound with a mass of 254.115 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0229] 34. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 175.0633 g / mol, the compound with a mass of 224.084 g / mol, the compound with a mass of 232.004 g / mol, the compound with a mass of 315.2409 g / mol and the compound with a mass of 702.5682 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0230] 35. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 175.0633 g / mol, the compound with a mass of 208.0737 g / mol and the compound with a mass of 254.1153 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0231] 36. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 175.0633 g / mol, the compound with a mass of 224.084 g / mol, the compound with a mass of 254.1153 g / mol and the compound with a mass of 315.2409 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0232] 37. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 175.0633 g / mol, the compound with a mass of 208.0737 g / mol, the compound with a mass of 315.2409 g / mol and the compound with a mass of 702.5682 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0233] 38. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 175.0633 g / mol and the compound with a mass of 315.2409 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0234] 39. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 208.0737 g / mol, the compound with a mass of 232.004 g / mol and the compound with a mass of 315.2409 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0235] 40. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 175.0633 g / mol and the compound with a mass of 208.0737 g / mol is determined in (a) and (b), the change compared to is determined in (c), and the analysis is performed in (d).

[0236] 41. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 175.0633 g / mol and the compound with a mass of 208.0737 g / mol is determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0237] 42. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 208.0737 g / mol and the compound with a mass of 702.5682 g / mol is determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0238] 43. The method according to any one of embodiments 25 to 30, wherein at least the amount of the compound with a mass of 175.0633 g / mol, the compound with a mass of 208.0737 g / mol and the compound with a mass of 315.2409 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0239] 44. The method according to any one of embodiments 25 to 30, wherein at least the amounts of the compound with a mass of 110.0367 g / mol, the compound with a mass of 232.004 g / mol, the compound with a mass of 254.1153 g / mol, the compound with a mass of 189.9936 g / mol, the compound with a mass of 189.0096 g / mol and the compound with a mass of 224.084 g / mol are determined in (a) and (b), the change compared to the amount is determined in (c), and the analysis is performed in (d).

[0240] 45. The method according to any one of embodiments 25 to 30, wherein at least the amounts of the compound with a mass of 110.0367 g / mol, the compound with a mass of 110.0367 g / mol, the compound with a mass of 175.0633 g / mol, the compound with a mass of 702.5682 g / mol, the compound with a mass of 208.0737 g / mol, the compound with a mass of 315.2409 g / mol, the compound with a mass of 232.004 g / mol and the compound with a mass of 254.1153 g / mol are determined in (a) and (b), the change compared to the above is determined in (c), and the analysis is performed in (d).

[0241] 46. ​​A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0242] (a) determining in a first bodily fluid sample of the subject an amount of at least one compound having a mass in grams per mole selected from the group consisting of: 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.345, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.0 452, 212.0536, 234.1832, 236.1049, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 319.2486, 331.2545, 332.1372, 334.2146, 339.3135, 346.1528, 350.0956, 366.0912, 371.8758, 440.2751, 538.1752, 540.2563 and 782.5638 (Group 1);

[0243] (b) determining the amount of at least one compound as in (a) in a second bodily fluid sample of the subject;

[0244] (c) comparing the amount of the at least one compound determined according to (a) to a corresponding amount of the at least one compound determined according to (b), wherein a change in the amount of the at least one compound according to (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia;

[0245] The first body fluid sample is obtained before administering thiethylperazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0246] 47. The method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to embodiment 46, wherein at least one compound having a mass in grams / mole is selected from the group consisting of 110.0367, 232.004, 224.084, 254.1153, 189.9936 and 189.0096 (Group 2).

[0247] 48. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to embodiment 46 or 47, wherein at least the amount of the compound having a mass of 110.0367 g / mol is determined in (a) and (b) and compared in (c).

[0248] 49. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 48, wherein in steps (a) and (b) the amounts of at least two compounds, preferably at least three compounds, more preferably at least four compounds, more preferably at least five compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject and compared in (c), wherein a change in the amount of each of the at least two compounds, preferably each of the at least three compounds, more preferably each of the at least four compounds, more preferably each of the at least five compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia, wherein more preferably one of the at least two compounds, preferably one of the at least three compounds, more preferably one of the at least four compounds, more preferably one of the at least five compounds is a compound with a mass of 110.0367 grams per mole.

[0249] 50. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 49, wherein in steps (a) and (b) the amounts of at least two compounds, preferably at least six compounds or at least seven compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject and compared in (c), wherein a change in the amount of each of the at least two compounds, preferably each of the at least six compounds, more preferably each of the at least seven compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia, wherein more preferably one of the at least two compounds, more preferably one of the at least six compounds or one of the at least seven compounds is a compound with a mass of 110.0367 grams per mole.

[0250] 51. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 50, wherein in steps (a) and (b) the amount of at least one other compound is additionally determined in the first body fluid sample of the subject, the at least one other compound having a PCR product selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477 and 97.9769 (Group 3) ), more preferably a mass in grams / mole selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4), and compared in (c), wherein the change in the amount of at least one compound according to (b) compared to the amount determined in (a) and the change in the amount of at least one other compound according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0251] 52. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0252] (a) determining the amount of at least two compounds having a mass in grams / mole selected from the group consisting of Group 3 in a first bodily fluid sample of the subject;

[0253] (b) determining the amounts of at least two of the same compounds as in (a) in a second bodily fluid sample from the subject;

[0254] (c) comparing the amounts of the at least two compounds determined according to (a) with the corresponding amounts of the at least two compounds determined according to (b), wherein a change in the amounts of the at least two compounds according to (b) compared to the amounts determined in (a) is indicative of Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia;

[0255] The first body fluid sample is obtained before administering thiethylperazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0256] 53. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 189.0096 g / mole, a compound with a mass of 224.084 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0257] 54. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 189.993 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 254.115 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0258] 55. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 232.004 g / mole, a compound with a mass of 315.2409 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0259] 56. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 12.5% ​​in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0260] 57. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 254.1153 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0261] 58. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 315.2409 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 12.5% ​​in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0262] 59. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 2% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0263] 60. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0264] 61. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amount of a compound with a mass of 175.0633 g / mole and a compound with a mass of 208.0737 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 12.5% ​​in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0265] 62. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole and a compound with a mass of 208.0737 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0266] 63. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amount of a compound with a mass of 208.0737 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0267] 64. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 40% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0268] 65. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 232.004 g / mole, a compound with a mass of 254.1153 g / mole, a compound with a mass of 189.9936 g / mole, a compound with a mass of 189.0096 g / mole and a compound with a mass of 224.084 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 1% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0269] 66. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 46 to 51, wherein in steps (a) and (b) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole, a compound with a mass of 702.5682 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 315.2409 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject and compared in (c), wherein a change of at least 2% in the amount of each of these compounds according to (b) compared to the amount determined in (a) indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0270] 67. A method for identifying a subject suffering from Alzheimer's dementia (AD), the method comprising:

[0271] (a) determining in a bodily fluid sample of the subject an amount of at least one compound having a mass in grams per mole selected from the group consisting of: 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.345, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.04 52, 212.0536, 234.1832, 236.1049, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 319.2486, 331.2545, 332.1372, 334.2146, 339.3135, 346.1528, 350.0956, 366.0912, 371.8758, 440.2751, 538.1752, 540.2563 and 782.5638 (Group 1);

[0272] (b) comparing the amount of the at least one compound determined according to (a) with an average amount in healthy subjects, wherein a change in the amount of the at least one compound according to (a) compared to the average amount in healthy subjects, preferably a change of at least 3% based on the average amount in healthy subjects as 100%, is indicative of Alzheimer's dementia in the subject or that the subject is at risk of developing Alzheimer's dementia;

[0273] The body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0274] 68. The method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to embodiment 67, wherein at least one compound having a mass in grams / mole is selected from the group consisting of 110.0367, 232.004, 224.084, 254.1153, 189.9936 and 189.0096 (Group 2).

[0275] 69. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to embodiment 67 or 68, wherein at least the amount of the compound having a mass of 110.0367 in grams per mole is determined in (a) and (b) and compared in (c).

[0276] 70. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 69, wherein in step (a) the amounts of at least two compounds, preferably at least three compounds, more preferably at least four compounds, more preferably at least five compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject and compared in (b), wherein a change in the amount of each of the at least two compounds, preferably each of the at least three compounds, more preferably each of the at least four compounds, more preferably each of the at least five compounds indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia, wherein more preferably one of the at least two compounds, preferably one of the at least three compounds, more preferably one of the at least four compounds, more preferably one of the at least five compounds is a compound having a mass in grams per mole of 110.0367.

[0277] 71. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 70, wherein in step (a) the amounts of at least two compounds, preferably at least six compounds, more preferably at least seven compounds having a mass in grams per mole selected from the group consisting of Group 1 or Group 2 are determined in a first body fluid sample of the subject and compared in (b), wherein a change in the amount of each of the at least two compounds, preferably each of the at least six compounds, more preferably each of the at least seven compounds indicates Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia, wherein more preferably one of the at least two compounds, more preferably one of the at least six compounds or one of the at least seven compounds is a compound having a mass in grams per mole of 110.0367.

[0278] 72. The method for identifying a subject suffering from or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 71, wherein in steps (a) and (b) the amount of at least one other compound is determined in the first body fluid sample of the subject, the at least one other compound having a PCR product selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477 and 97.9769 (Group 3), more preferably selected from the group consisting of 208.073 7, 315.2409, 175.0633, 702.5682 (Group 4) and compared in (c), wherein a change in the amount of at least one compound according to (b) compared to the amount determined in (a) and a change in the amount of at least one other compound according to (a) compared to the average amount in healthy subjects, preferably a change of at least 3% based on the average amount in healthy subjects as 100%, indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0279] 73. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising:

[0280] (a) determining the amount of at least two compounds having a mass in grams / mole selected from the group consisting of Group 3, preferably selected from the group consisting of Group 4, in a body fluid sample of a subject;

[0281] (b) comparing the amounts of the at least two compounds determined according to (a) with the average amounts in healthy subjects, wherein a change in the amounts of the at least two compounds according to (a) compared to the average amounts in healthy subjects, preferably a change of at least 3% based on the average amounts in healthy subjects as 100%, is indicative of Alzheimer's dementia in the subject or of the subject being at risk of developing Alzheimer's dementia;

[0282] The body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0283] 74. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 189.0096 g / mole, a compound with a mass of 224.084 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0284] 75. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 189.993 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 254.115 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0285] 76. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 232.004 g / mole, a compound with a mass of 315.2409 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0286] 77. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole, and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0287] 78. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole, a compound with a mass of 224.084 g / mole, a compound with a mass of 254.1153 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0288] 79. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 315.2409 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0289] 80. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0290] 81. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0291] 82. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amount of a compound with a mass of 175.0633 g / mole and a compound with a mass of 208.0737 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0292] 83. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole, and a compound with a mass of 208.0737 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0293] 84. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amount of a compound with a mass of 208.0737 g / mole and a compound with a mass of 702.5682 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 12% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0294] 85. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 175.0633 g / mole, a compound with a mass of 208.0737 g / mole, and a compound with a mass of 315.2409 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0295] 86. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 232.004 g / mole, a compound with a mass of 254.1153 g / mole, a compound with a mass of 189.9936 g / mole, a compound with a mass of 189.0096 g / mole and a compound with a mass of 224.084 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0296] 87. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein in step (a) at least the amounts of a compound with a mass of 110.0367 g / mole, a compound with a mass of 110.0367 g / mole, a compound with a mass of 175.0633 g / mole, a compound with a mass of 702.5682 g / mole, a compound with a mass of 208.0737 g / mole, a compound with a mass of 315.2409 g / mole, a compound with a mass of 232.004 g / mole and a compound with a mass of 254.1153 g / mole are determined in a first body fluid sample of the subject and compared in (b), wherein a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia in the subject or the risk of the subject developing Alzheimer's dementia.

[0297] 88. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to any one of embodiments 67 to 72, wherein the average amount of the healthy subject value is a reference value for healthy subjects from the literature, or a reference value previously determined from healthy subjects, or a reference value from a body fluid sample of the subject before TEP administration.

[0298] 89. A method according to any one of embodiments 1 to 88, wherein the quantity determination in any of steps (a) and / or (b) is performed by mass spectrometry (MS), preferably by tandem mass spectrometry (MS / MS), more preferably by tandem mass spectrometry combined with prior liquid chromatography (LC-MS / MS).

[0299] 90. A method according to any one of embodiments 1 to 89, which is an in vitro method.

[0300] 91. The method of any one of embodiments 1 to 90, wherein the subject is human.

[0301] 92. A method according to any one of embodiments 1 to 91, wherein the body fluid sample is selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, preferably the body fluid sample is a blood sample; and the first body fluid sample and the second body fluid sample are independently selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, respectively, wherein preferably, the first body fluid sample and the second body fluid sample are samples of the same type and are both selected from the group consisting of a blood sample, a urine sample, a liquid sample (CSF) and a mixture of two or more thereof, wherein more preferably, the first body fluid sample and the second body fluid sample are each blood samples (first blood sample and second blood sample).

[0302] 93. At least one compound having a mass in grams / mole selected from the group consisting of Group 1 or (Group 2) or as defined in any one of Embodiments 1 to 92, and optionally in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3, preferably selected from the group consisting of Group 4, for use in diagnosing AD in a subject or for determining the risk of a subject developing AD.

[0303] 94. At least one compound for use according to embodiment 93, wherein at least two compounds having a mass in g / mol selected from the group consisting of Group 1 or Group 2 as defined in any one of embodiments 1 to 92 are used, preferably at least three compounds having a mass in g / mol selected from the group consisting of Group 1 or Group 2 as defined in any one of embodiments 1 to 92, more preferably at least four compounds having a mass in g / mol selected from the group consisting of Group 1 or Group 2 as defined in any one of embodiments 1 to 92; more preferably at least five compounds having a mass in g / mol selected from the group consisting of Group 1 or Group 2 as defined in any one of embodiments 1 to 92;

[0304] Each is optionally combined with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4.

[0305] 95. At least one compound for use according to embodiment 93, wherein at least two compounds having a mass in g / mol selected from the group consisting of Group 1 or Group 2 as defined in any one of embodiments 1 to 92, preferably at least six compounds having a mass in g / mol selected from the group consisting of Group 1 or Group 2 as defined in any one of embodiments 1 to 92, more preferably at least seven compounds having a mass in g / mol selected from the group consisting of Group 1 or Group 2 as defined in any one of embodiments 1 to 92 are used;

[0306] Each is optionally combined with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4.

[0307] 96. At least two compounds having masses in grams / mole selected from the group consisting of Group 3 or Group 4 for use in diagnosing AD in a subject or in determining the risk of a subject developing AD.

[0308] Second diagnostic use (alternative wording)

[0309] 97. Use of at least one compound having a mass in grams / mole selected from the group consisting of Group 1 or Group 2 as defined in any one of Embodiments 1 to 92 in a sample of a subject, and optionally in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4, for diagnosing AD in the subject or for determining the risk of the subject developing AD.

[0310] 98. The use according to embodiment 97, wherein a sample from a subject having a mass in grams / mole of at least two, preferably at least three, more preferably at least four, more preferably at least five compounds selected from the group consisting of Group 1 or Group 2 as defined in any one of embodiments 1 to 93, and optionally in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4 is used for diagnosing AD in the subject or for determining the risk of the subject developing AD.

[0311] 99. The use according to embodiment 97, wherein a sample from a subject having a mass in grams / mole of at least two, preferably at least six, more preferably at least seven compounds selected from the group consisting of Group 1 or Group 2 as defined in any one of embodiments 1 to 92, and optionally in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4 is used for diagnosing AD in the subject or for determining the risk of the subject developing AD.

[0312] 100. Use of at least two compounds having masses in grams / mole selected from the group consisting of Group 3 or Group 4 in a sample of a subject for diagnosing AD in the subject or for determining the risk of the subject developing AD.

[0313] 101. An apparatus suitable for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the apparatus comprising:

[0314] (a) an analytical unit capable of determining the amount of at least one compound having a mass in grams / mole selected from the group consisting of Group 1 in a first body fluid sample of a subject;

[0315] (b) a data processor for analyzing the determined amount of at least one compound using a prediction algorithm implemented in the data processor, the prediction algorithm being capable of predicting AD in the subject based on the at least two compounds, thereby identifying a subject having AD if AD is predicted, or identifying a subject at risk of developing Alzheimer's dementia if AD is predicted.

[0316] 102. A kit for identifying subjects having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the kit comprising a reference sample having a mass in grams / mole of at least one compound selected from the group consisting of Group 1 or Group 2, optionally a reference sample having a mass in grams / mole of at least one compound selected from the group consisting of Group 3, or optionally a reference sample having a mass in grams / mole of at least one compound selected from the group consisting of Group 4, and optionally one or more reagents for sample preparation and / or extraction.

[0317] The present invention is further illustrated by the following reference examples, comparative examples and embodiments. Example

[0318] The following examples are intended to illustrate the present invention only and should not be construed as limiting the scope of the present invention in any way.

[0319] I-Method

[0320] I.1 Treatment

[0321] 15 human subjects (7 healthy, 8 with Alzheimer's disease) were treated with 6.5 mg of thioethylperazine (TEP). Blood samples were collected at 0, 0.5, 1, 1.5, 2, 4 and 8 hours after administration. AD subjects were classified by a Mini-Mental State Examination (MMSE) score of 25-18. In addition, AD diagnosis was confirmed by the recommended examination according to the German DGN / DGPPN S3 guideline "Dementia" and by the following:

[0322] -Psychological and cognitive testing

[0323] - Lumbar puncture for subjects with uncertain AD diagnosis after CNS imaging

[0324] - Clinical Dementia Rating (overall CDR) of 0.5 or 1 and a Memory Box score of at least 0.5.

[0325] - Isolated or major episodic memory loss, as evidenced by memory performance on the Logical Memory subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale-III being 1 standard deviation below the age-adjusted norm.

[0326] I.2 Blood sampling

[0327] A sample of 10 ml of venous blood was collected into a standardized test tube containing EDTA and gently shaken 1-2 times. The sample was centrifuged at 1600 g for 10 minutes at room temperature as quickly as possible (within 30 minutes at most). The plasma was aliquoted into 6 portions (0.5 ml). All aliquots were frozen in a deep freezer (-80 ° C) within 10 minutes after centrifugation and stored until use.

[0328] I.3 Untargeted metabolomics

[0329] All procedures performed in this section were performed by BGI Genomics. Non-targeted metabolomics refers to the high-throughput analysis of the metabolic state of biological systems (see Matthaios-Emmanouil P Papadimitropoulos, Catherine G Vasilopoulou, Christoniki Maga-Nteve, Maria I Klapa in Methods Mol Biol. 2018; 1738:133-147; doi: 10.1007 / 978-1-4939-7643-0_9.).

[0330] 1 Main instruments and reagents

[0331] Ultra-high performance liquid chromatography: Waters 2D UPLC, Waters, USA

[0332] High-resolution mass spectrometer: Q Exactive, Thermo Fisher Scientific, USA

[0333] Chromatographic column: ACQUITY UPLC BEH C18 1.7 μm, 2.1*100 mm, Waters, USA

[0334] Low temperature high speed centrifuge: Centrifuge 5430, Eppendorf

[0335] Vortex instrument: QL-901, Kylin-bell Lab Instruments Co., Ltd., China

[0336] Ultrapure water system: Milli-Q Integral, Millipore Corporation, USA

[0337] Vacuum concentrator: Maxi Vacbeta, GENE COMPANY

[0338] Internal standard mixture (IS) contains: L-leucine-d3, L-phenylalanine (13C9, 99%), L-tryptophan-d5, progesterone-2,3,4-13C3

[0339] MS grade methanol (A454-4) and acetonitrile (A996-4) were purchased from Thermo Fisher Scientific (USA). Formic acid was purchased from DIMKA (50144-50 ml, USA), and ammonium formate (17843-250 G, Honeywell Fluka, USA) was obtained from Fluka. Ultrapure water was filtered through a Milli-Q system.

[0340] 2 Metabolite extraction

[0341] Metabolite extraction was performed mainly according to previously reported methods [[4][5]. Briefly, 100 μL of plasma samples were extracted by directly adding 300 μL of pre-cooled methanol and acetonitrile (2:1, v / v), and internal standard mixture 1 (IS1) and internal standard mixture 2 (IS2) were added for quality control of sample preparation. After vortexing for 1 minute and incubating at -20 °C for 2 hours, the samples were centrifuged at 4000 rpm for 20 minutes, and the supernatant was transferred for vacuum freeze drying. The metabolites were resuspended in 150 μL of 50% methanol and centrifuged at 4000 rpm for 30 minutes, and the supernatant was transferred to an autosampler vial for LC-MS analysis. Quality control (QC) samples were prepared by pooling the same volume of each sample to evaluate the reproducibility of the entire LC-MS analysis.

[0342] 3LC-MS / MS analysis

[0343] 3.1. Chromatographic conditions

[0344] The samples were analyzed on a Waters 2D UPLC (Waters, USA), which was coupled to a Q-Exactive mass spectrometer (Thermo Fisher Scientific, USA) with a heated electrospray ionization (HESI) source and controlled by the Xcalibur 2.3 software program (Thermo Fisher Scientific, Waltham, MA, USA). Chromatographic separation was performed on a Waters ACQUITY UPLC BEH C18 column (1.7 μm, 2.1 mm × 100 mm, Waters, USA), and the column temperature was maintained at 45 °C. In the positive mode, the mobile phase consisted of 0.1% formic acid (A) and acetonitrile (B), and in the negative mode, the mobile phase consisted of 10 mM ammonium formate (A) and acetonitrile (B). Gradient conditions were as follows: 0-1 min, 2% B; 1-9 min, 2%-98% B; 9-12 min, 98% B; 12-12.1 min, 98% B to 2% B; and 12.1-15 min, 2% B. The flow rate was 0.35 mL / min, and the injection volume was 5 μL.

[0345] 3.2 Mass spectrometry conditions

[0346] The MS settings for positive / negative ionization mode were as follows: spray voltage: 3.8 / -3.2 kV; sheath gas flow: 40 arbitrary units (arb); aux gas flow: 10 arb; aux gas heater temperature: 350 °C; capillary temperature: 320 °C. The full scan range was 70-1050 m / z with a resolution of 70,000 and the automatic gain control (AGC) target for MS acquisition was set to 3e6 with a maximum ion injection time of 100 ms. The first 3 precursors were selected for subsequent MSMS fragmentation with a maximum ion injection time of 50 ms and a resolution of 17,500 with an AGC of 1e5. The stepped normalized collision energy was set to 20, 40, and 60 eV.

[0347] To provide more reliable experimental results during instrument testing, samples were randomly ordered to reduce systematic errors. One QC sample was interspersed with every 10 samples.

[0348] 4 Data Preprocessing

[0349] The mass spectrometry raw data (raw files) collected by LC-MS / MS were imported into Compound Discoverer 3.1 (Thermo Fisher Scientific, USA) for data processing, which included: peak extraction, retention time correction within and between groups, additive ion pooling, missing value filling, background peak labeling, and metabolite identification. Finally, information about the molecular weight, retention time, peak area, and identification results of the compound was exported. The identification of metabolites was a comprehensive result of the BGI self-built standard library, mzCloud, and ChemSpider (HMDB, KEGG, LipidMaps) databases.

[0350] The results exported from Compound Discoverer 3.1 were imported into metaX for data preprocessing, which included: 1. Normalizing the data using Probabilistic Quotient Normalization (PQN [6]) to obtain relative peak areas. 2. Correcting for batch effects using QC-RLSC [[4] (Quality control-based robust LOESS signal correction); 3. Calculating the CV (coefficient of variation) of the relative peak areas in all QC samples, and removing compounds with a CV greater than 30%. Probability quotient normalization (PQN): Probability quotient normalization is to calculate the average of all QC samples for each feature to obtain a reference vector; calculate the median between the reference vector and each sample, and obtain the coefficient vector associated with each sample, and then normalize each sample by dividing it by the median of the coefficient vector (the median is different for each sample).

[0351] QC-RLSC [[4]]: Local polynomial regression fitting signal correction (QC-RLSC) based on QC sample information.

[0352] Data quality was assessed by the repeatability of QC sample testing, including chromatogram overlap, PCA, peak number, and peak response intensity differences of QC samples.

[0353] 5 Partial Least Squares-Discriminant Analysis (PLS-DA)

[0354] The partial least squares regression method was used to establish a relationship model between metabolite expression and sample category to achieve modeling prediction of sample category. A PLS-DA model between the comparison groups (two groups) was established after log2-log transformation of the data, and the method used for scaling was Par. A 7-fold cross-validation was performed during modeling. In order to evaluate the model, the PLS-DA model [7] [8] was subjected to 200 response permutations.

[0355] Data were used for fold change analysis and T test. Fold change (FC) was obtained by fold change analysis, and p-values ​​were obtained by Student's T test, where p-values ​​were corrected for false discovery rate (FDR) to obtain q-values.

[0356] Comparisons were made between healthy probands before thiethylperazine administration and probands with Alzheimer's disease before thiethylperazine administration, and between healthy probands after thiethylperazine administration and probands with Alzheimer's disease after thiethylperazine administration.

[0357] 6 Databases and Identification

[0358] Databases used for compound identification include: mzCloud, Chemspider, Human Metabolome Database (HMDB), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Lipidmaps database.

[0359] II Identification of metabolites / masses with diagnostic value

[0360] 1. Software

[0361] Python 3.9.5 running in Spyder 5.3.2 IDE with the following libraries: scikit-learn, pandas, and numpy. Windows 11, Microsoft Excel 365.

[0362] 2. Data processing and filtering

[0363] After processing all blood samples using the untargeted metabolomics program, the area under the curve (AUC) value for each mass (x) was normalized using the following formula:

[0364] z = (x - u) / s

[0365] Where u is the mean of all samples and s is the standard deviation of all samples. The normalized data represent dataset 1.

[0366] Afterwards, a correlation analysis of all masses within Dataset 1 was performed. In cases where an absolute pairwise correlation was found to exceed 0.95, one of the masses in the pair was excluded from further analysis. The remaining data represents Dataset 2.

[0367] Then, after running PLS-DA, Dataset 2 was successively filtered for the following qualities based on Student’s T-test: (i) between healthy subjects and AD subjects at the pre-TEP time point no Significantly different masses and (ii) at post-TEP time points yes Significantly different quality to generate dataset 3.

[0368] Dataset 3 was then checked for masses that were found to have highly correlated masses in Dataset 1. Four such masses were identified, and the correlated masses that were excluded from Dataset 2 were reintroduced into Dataset 3 to yield a final dataset containing 45 masses.

[0369] 3. Analyze the predictive value of individual masses

[0370] For better visualization, the AUC data 2 h after TEP administration for each of the selected 45 masses were normalized to the corresponding mean value of healthy individuals (X 质量i = AUC 质量I * 100 / average 所有健康质量i ). 32 masses were significantly different in samples taken from AD subjects compared to samples from healthy subjects. For 42 of the 45 masses, an absolute change of 3% (relative to the mean of healthy subjects) was sufficient to diagnose AD with an accuracy of at least 67% (Table 1).

[0371] Table 1

[0372]

[0373] Table 1-Continued 1

[0374]

[0375] Table 1-Continued 2

[0376]

[0377] Table 1-Continued 3

[0378]

[0379] Table 1-Continued 4

[0380]

[0381] 4. Screening of quality combinations that predict disease status

[0382] To improve the accuracy and robustness of this diagnostic approach, the final dataset was further analyzed and processed using a supervised machine learning algorithm to evaluate the diagnostic potential of all possible combinations of up to 7 masses (excluding combinations that would contain highly correlated masses) and extract combinations with high diagnostic value. Due to the small cohort size, a rigorous approach of training and testing classifier models has been utilized to estimate the diagnostic robustness of specific mass combinations for unknown samples.

[0383] The scikit-learn GridSearch pipeline with a nested cross-validation method was used to evaluate the best quality combinations and classifiers for identifying AD patients. Within the GridSearch pipeline, the following supervised learning methods were screened: logistic regression, stochastic gradient descent classifier (SGD classifier), decision tree classifier, random tree classifier, extreme tree classifier, AdaBoost classifier, multilayer perceptron classifier (MLP classifier), gradient boosting classifier, Gaussian naive Bayes (GaussianNB), K-nearest neighbor classifier, C-support vector classification (SVC), quadratic discriminant analysis, and linear regression. For each method, hyperparameter optimization and training were performed on 70% of the complete dataset using stratified three-fold data splitting (inner loop). The classifier with the highest area under the ROC curve (AUC) was then evaluated on the remaining 30% of the dataset using the leave-one-out method (outer loop) to assess the generalizability and accuracy of the model and quality combination.

[0384] result

[0385] Screening indicated that, among the 45 qualities found, a large number of combinations of 1 to 7 were most valuable for accurate prediction of disease status. Table 2 below shows an exemplary selection of quality combinations that predict disease status with high accuracy. Since the calculation of the predictions of most classifiers is difficult or impossible to depict, only the logistic regression algorithm was selected for this Table 2. However, in most cases, the decisive factor for accurate prediction is the combination of qualities, and no algorithms for prediction, which again highlights the effectiveness of the chosen qualities. This fact is exemplified in Table 4, where the key diagnostic parameters of different classifiers using the same combination of qualities are shown.

[0386] For disease prognosis, the logistic regression equation should be interpreted as follows:

[0387] y = I + C1*F1 + C2*F2 +…+ Cn *F n ,

[0388] where I is the intercept, and C n is the quality F n The coefficient of . Positive y values ​​are predictions of Alzheimer's disease, while negative values ​​predict the non-diseased state. Larger absolute values ​​mean greater certainty in the prediction.

[0389] For example, in the case of the first mass combination shown in Table 2, the formula is as follows:

[0390]

[0391] where [FeatX] is the concentration of the corresponding mass in the sample (standard scaled value or absolute value).

[0392] Table 2

[0393]

[0394]

[0395] Without being bound by this theory, it is believed that of the 45 compounds represented above by mass in grams / mole, the following 5 compounds are related to the chemical compounds listed in Table 3 below:

[0396] Table 3

[0397] Compounds with a specific mass (in grams / mole) related to their structure

[0398]

[0399] Table 4

[0400]

[0401]

[0402] References

[0403] [1] US 2015 / 0374711 A1.

[0404] [2] Schindler SE, Bollinger JG, Ovod V, et al. High-precision plasma beta-amyloid 42 / 40 predicts current and future brain amyloidosis. Neurology 2019, 93(17): e1647-e1659.

[0405] [3] Eugenia Trushina E, Dutta T, Persson XM T, Mielke MM, Petersen RC, Identification of Altered Metabolic Pathways in Plasma and CSF in Mild Cognitive Impairment and Alzheimer's Disease Using Metabolomics. PlosOne, May 2013, Vol. 8, No. 5, e63644.

[0406] [4] Dunn WB, Broadhurst D, Begley P, et al. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nature Protocols, 2011, 6(7): 1060-1083.

[0407] [5] Sarafian MH, Gaudin M, Lewis MR, et al., Objective Set of Criteria for Optimization of Sample Preparation Procedures for Ultra-High Throughput Untargeted Body fluid Plasma Lipid Profiling by Ultra Performance Liquid Chromatography-Mass Spectrometry. Analytical Chemistry, 2014, 86(12): 5766-5774.

[0408] [6] Guida RD, Engel J, Allwood JW, et al. Non-targeted UHPLC-MS metabolomics data processing methods: a comparative investigation of normalisation, missing value imputation, transformation and scaling. Metabolomics, 2016, 12(5): 93.

[0409] [7] Barker, M.; Rayens, W., Partial least squares for discrimination. J Chemometr 2003, 17(3): 166-173.

[0410] [8] Westerhuis JA, Hoefsloot HCJ, Smit S, et al., Assessment of PLSDA cross validation[J]. Metabolomics, 2008, 4(1):81-89.

Claims

1. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising: (a) determining in a first bodily fluid sample of the subject at least an amount of a compound having a mass of 110.0367 in grams per mole; (b) determining the amount of the same compound as in (a) in a second bodily fluid sample of the subject; (c) determining a change in the amount of the compound determined according to (a) compared to the corresponding amount of the compound determined according to (b); (d) analyzing the changes determined in (c) using a computer-implemented prediction algorithm capable of predicting AD in a subject based on the compound, thereby identifying a subject suffering from AD or at risk of developing Alzheimer's dementia if AD is predicted; The first body fluid sample is obtained before administering thiethylperazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

2. The method for identifying a subject suffering from or at risk of developing Alzheimer's dementia according to claim 1, wherein the first body fluid sample is derived from the subject after thiethylperazine or a pharmaceutically acceptable salt thereof is administered to the subject.

3. A method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia according to claim 1 or 2, wherein in step (a) the amount of at least one other compound is additionally determined in the first body fluid sample of the subject and in step (b) the amount of at least one other compound is additionally analyzed, the mass of the at least one other compound in grams / mole being selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4).

4. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia according to any one of claims 1 to 3, wherein the computer-implemented prediction algorithm uses a supervised machine learning algorithm that has been trained with a training data set comprising quantitative or qualitative data of the following compounds in body fluid samples from subjects known to suffer from AD and subjects known not to suffer from AD: A compound having a mass in g / mol of 110.0367, optionally in combination with at least one other compound from group 4.

5. The method according to any one of claims 1 to 4, wherein at least the amount of the compound with a mass of 110.0367 g / mol, the compound with a mass of 175.0633 g / mol and the compound with a mass of 208.0737 g / mol is determined in (a) and analyzed in (b).

6. A method for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the method comprising: (a) determining an amount of a compound having a mass of 110.0367 in grams per mole in a first bodily fluid sample of the subject; (b) determining the amount of the same compound as in (a) in a second bodily fluid sample of the subject; (c) comparing the amount of the compound determined according to (a) with the corresponding amount of the compound determined according to (b), wherein a change in the amount of the compound according to (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia in the subject or a risk of the subject developing Alzheimer's dementia; The first body fluid sample is obtained before administering thiethylperazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

7. A method for identifying a subject suffering from Alzheimer's dementia (AD), the method comprising: (a) determining in a body fluid sample of the subject an amount of a compound having a mass of 110.0367 in grams per mole; (b) comparing the amount of the compound determined according to (a) with an average amount in healthy subjects, wherein a change in the amount of the compound according to (a) compared to the average amount in healthy subjects, preferably a change of at least 3% based on the average amount in healthy subjects as 100%, is indicative of Alzheimer's dementia in the subject or of the subject being at risk of developing Alzheimer's dementia; The body fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

8. A compound having a mass in g / mol of 110.0367, and optionally in combination with at least one compound having a mass in g / mol selected from Group 4, for use in diagnosing AD in a subject or in determining the risk of a subject developing AD.

9. Use of at least one compound having a mass of 110.0367 in g / mol in a sample of a subject, optionally in combination with at least one compound having a mass in g / mol selected from Group 4, for diagnosing AD in the subject or for determining the risk of the subject developing AD.

10. An apparatus suitable for identifying a subject having Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the apparatus comprising: (a) an analytical unit capable of determining the amount of at least one compound having a mass of 110.0367 in grams / mole in a first bodily fluid sample of the subject; (b) a data processor for analyzing the determined amounts of the compounds using a prediction algorithm implemented in the data processor, the prediction algorithm being capable of predicting AD in a subject based on the at least two compounds, thereby identifying a subject having AD if AD is predicted, or identifying a subject at risk of developing Alzheimer's dementia if AD is predicted.

11. A kit for identifying subjects suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia, the kit comprising a reference sample of a compound having a mass of 110.0367 in grams / mole, optionally a reference sample of at least one compound having a mass in grams / mole selected from the group consisting of Group 4, and optionally one or more reagents for sample preparation and / or extraction.

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