Identifying subjects suffering from 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 Alzheimer's disease (AD) or at risk of developing Alzheimer's disease, the method comprising the steps of: (a) determining, in a first body fluid sample from the subject, an amount of a compound having a mass, in grams / mole, of at least 110.0367; (b) determining, in a second body fluid sample from the subject, an amount of the same compound as in (a); (c) determining a change in the amount of the compound determined according to (a) compared to the amount of each of the compounds determined according to (b); and (d) analyzing the change determined in (c) using a computer-implemented predictive algorithm capable of predicting AD in the subject based on the compounds, whereby, if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's disease; wherein the first body fluid sample is obtained before administration of thiethylperazine or a pharmaceutically acceptable salt thereof, and the second body fluid sample is obtained after administration of thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

Description

[Technical Field]

[0001] In a first aspect, the present invention provides a method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), comprising: (a) detecting a serotonin level, in grams / mole, of 110.0367, 232.004, 224.084, 254.1153, 189.9936, 189.0096, 155.007, 355.34 in a first body fluid sample from the subject; 5, 358.159, 109.0706, 110.0004, 145.0226, 166.0633, 178.0995, 190.0631, 191.0253, 200.0452, 212.0536, 234.1832, 236.1049, 259.9982, 285.1362, 291.0832, 301.1313, 314.1266, 318.1215, 31 In a second aspect, the present invention relates to a method for identifying a subject suffering from Alzheimer's disease (AD) or at risk of developing Alzheimer's disease, comprising the steps of: (a) determining the amount of at least one compound having a mass selected from the group consisting of 9.2486, 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 determined amount of the at least one compound using a computer-implemented predictive algorithm capable of predicting AD in a subject based on the at least one compound, whereby if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's disease. The third aspect of the present invention and the fourth aspect of the present invention both relate to methods of identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD).In a fifth aspect, the present invention relates to a second diagnostic use, and a sixth aspect of the invention is directed to a device adapted for identifying subjects suffering from or at risk of developing Alzheimer's dementia (AD), while a seventh aspect of the invention relates to a kit for identifying subjects suffering from or at risk of developing Alzheimer's dementia (AD). [Background technology]

[0002] Accumulation of proteins or protein fragments (peptides) in the brain is a key feature of age-related neurodegenerative diseases. In Alzheimer's disease (AD) and cerebral beta-amyloid angiopathy (CAA), aggregation of beta-amyloid peptides (Aβ) is thought to trigger the disease. Several active drugs, such as thiethylperazine [1], are known for the treatment of AD. Regarding diagnosis, higher levels of 40- and 42-amino acid Aβ peptides in the brain, partially reflected by increased levels of these peptides in the peripheral bloodstream, are used as a diagnostic indicator for Alzheimer's disease. However, quantification of Aβ in blood samples is unreliable, even using highly sensitive methods such as liquid chromatography coupled to mass spectrometry (LC-MS / MS), and requires Aβ immunoprecipitation as an additional, expensive step in sample preparation. Such assays have recently become publicly available and achieve approximately 77% accuracy in predicting brain amyloid status indicative of AD in patients between the ages of 65 and 75 years, with the accuracy decreasing with age [2]. Another study by E. Trushina et al. using UPLC-ToF-MS-based metabolomics analyzed and compared metabolite profiles in plasma and cerebrospinal fluid samples from cognitively normal subjects, subjects with mild cognitive impairment, and patients with AD. [3] However, while early diagnosis is a catchphrase, it has been noted that current research cannot do more than distinguish between healthy and diseased subjects. Furthermore, there are further differences, such as which type of body fluid is investigated, since different metabolic markers are detected in plasma and cerebrospinal fluid. Summary of the Invention [Problem to be solved by the invention]

[0003] However, because AD pathology is hypothesized to begin up to 20 years before the onset of clinical symptoms, diagnostic methods are needed to detect signs of AD pathology in younger populations.

[0004] Therefore, the underlying technical problem was to provide means and methods that meet the aforementioned needs, in particular to provide a method for diagnosing or pre-diagnosing Alzheimer's dementia in a subject. [Means for solving the problem]

[0005] First Aspect - Method for Identifying a Subject Suffering from or at Risk for Developing Alzheimer's Dementia (AD) Accordingly, in a first aspect, the present invention provides a method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), comprising the steps of: (a) In the first body fluid sample of the subject, the values ​​in grams / mole were: 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, 236.1049, 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); (b) analyzing the determined amount of the at least one compound using a computer-implemented predictive algorithm capable of predicting AD in a subject based on the at least one compound, whereby, if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's dementia. The present invention relates to a method, comprising: DETAILED DESCRIPTION OF THE INVENTION

[0006] When used below, the terms "have," "comprise," or "include," or any grammatical variations thereof, are used in a non-exclusive manner. Thus, these terms can refer both to a situation in which, in addition to the features introduced by these terms, no further features are present in the entity described in this context, and to a situation in which one or more further features are present. As an example, the expressions "A has B," "A comprises B," and "A includes B" can refer both to a situation in which, in addition to B, no other elements are present in A (i.e., a situation in which A consists solely and exclusively of B), and to a situation in which, in addition to B, one or more further elements are present in entity A, such as element C, elements C and D, or even further elements.

[0007] Furthermore, when used hereinafter, the terms "preferably," "more preferably," "most preferably," "particularly," "more particularly," "particularly," "more particularly," or similar terms are used in conjunction with optional features without restricting further possibilities. Features introduced by these terms are therefore optional features and are not intended to limit the scope of the claims in any way. The present invention may also be implemented by using alternative features, as recognized by those skilled in the art. Similarly, features introduced by "in an embodiment of the present invention" or similar expressions are intended to be optional features, without any limitations on further embodiments of the invention, without any limitations on the scope of the invention, and without any limitations on the possibility of combining features introduced in this way with other optional or non-optional features of the invention.

[0008] The term "identifying a subject suffering from Alzheimer's dementia (AD)" is synonymous with "diagnosing Alzheimer's dementia (AD) in a subject." As used herein, both "identifying" and "diagnosing" refer to assessing whether or not a subject has a disease. Thus, the presence or absence of a disease in a subject can be diagnosed. Preferably, this term refers to determining whether the disease is likely or excluding the possibility of the disease. As will be understood by those skilled in the art, such assessment is preferably correct for 100% of the subjects studied, but this may not usually be the case. However, this term requires that a statistically significant portion of the subjects can be correctly assessed and thus diagnosed. Whether a portion is statistically significant can be determined without further ado by those skilled in the art using various well-known statistical evaluation tools, such as determining confidence intervals, determining p-values, Student's t-test, Mann-Whitney test, etc. 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 no greater than 0.2, no greater than 0.1 or no greater than 0.05.

[0009] The terms "identifying" and "diagnosing" include individual diagnosis of a disease or its symptoms, as well as ongoing monitoring of a patient. Monitoring, i.e., diagnosing the presence or absence of a disease or its associated symptoms at various points in time, includes monitoring of patients known to be suffering from the disease, as well as monitoring of subjects known to be at risk of developing the disease, such as subjects with a genetic predisposition to the disease or subjects determined to be at risk based on the methods identified above. Furthermore, monitoring can also be used to determine whether a patient is being successfully treated, or whether at least the symptoms of the disease can be improved over time with a particular therapy. Furthermore, monitoring can be used for active patient management, including decisions regarding hospitalization, intensive care treatment, and / or additional qualitative and quantitative monitoring procedures.

[0010] The term "identifying a subject at risk of developing Alzheimer's dementia" refers to assessing the probability that a subject will suffer from Alzheimer's dementia within a certain time window, i.e., a prediction window. This term preferably relates to predicting whether a subject is at increased risk of Alzheimer's dementia compared to the average risk of developing Alzheimer's dementia in a population of subjects, rather than giving an exact probability of risk of developing Alzheimer's dementia.

[0011] Alzheimer's disease (AD) (Morbus Alzheimer, Alzheimer's disease) is a neurodegenerative disease characterized by increased dementia. Current diagnostic criteria for determining whether a subject has AD are preferably based on amyloid positron emission tomography and / or cerebrospinal fluid diagnostics and / or cognitive testing. Biomarkers associated with AD are neurodegenerative biomarkers known to those skilled in the art, such as Abeta-40, Abeta-42, or the Abeta42 / 40 ratio in body fluids (blood, CSF), phosphorylated variants of Tau protein (e.g., p-Tau181, p-Tau217, etc.), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Methods for determining whether a subject is suffering from AD involve determining the subject's cognitive performance using one or more tests known to those skilled in the art, such as the ADAS-Cog, FCSRT, ADCS-iADL, QoL-AD, CDR, MMSE, etc.

[0012] The term "subject", as used herein, relates to a multicellular animal, preferably a vertebrate, more preferably a mammal, more preferably a human.

[0013] A "body fluid sample" is a sample from the group consisting of a blood sample, a urine sample, a cerebrospinal fluid sample (CSF) and a mixture of two or more thereof; preferably, the body fluid sample is a blood sample.

[0014] The method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD) is an in vitro method.

[0015] The term "determining the amount" refers to a determination based on mass spectrometry (MS). Mass spectrometry, as used herein, encompasses all techniques that allow for the determination of molecular weights (i.e., masses) or mass variables corresponding to compounds, i.e., metabolic analytes. More preferably, mass spectrometry, as used herein, refers to GC-MS, LC-MS, direct infusion mass spectrometry, FT-ICR-MS, CE-MS, HPLC-MS, quadrupole mass spectrometry, any sequentially coupled mass spectrometry, e.g., MS-MS or MS-MS-MS, ICP-MS, Py-MS, TOF, or any combination approach using the aforementioned techniques. How to apply these techniques is well known to those skilled in the art. Furthermore, suitable devices are commercially available. More preferably, mass spectrometry, as used herein, refers to LC-MS and / or GC-MS, i.e., mass spectrometry operably coupled to a previous 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 any technique that allows the separation of compounds (e.g., at least two metabolic analytes to be determined according to the present invention) in a liquid or supercritical phase. Liquid chromatography is characterized by the passage of compounds in a mobile phase through a stationary phase. When compounds pass through the stationary phase at different speeds, each individual compound has its own specific retention time (i.e., the time required for the compound to pass through the system), and the compounds are separated over time. Liquid chromatography, as used herein, also includes HPLC. Devices for liquid chromatography are commercially available, for example, from Agilent Technologies, USA. Specific compounds and their specific masses, as well as their amounts, are determined based on the associated peaks in the mass spectrum. Such peaks contain characteristic information of the compound, i.e., m / z information, and an intensity value related to the abundance (i.e., amount) of the compound in the sample.

[0016] In some preferred embodiments of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the 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).

[0017] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), at least a compound having a mass in grams / mole of 110.0367 is determined in (a), and the determined amount is analyzed in (b).

[0018] In some preferred embodiments of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), 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), 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.

[0019] In some preferred embodiments of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), 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), 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.

[0020] In some preferred embodiments of the method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the amount of at least one additional 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 from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4), is further determined in the subject's first body fluid sample in step (a) and further analyzed in (b).

[0021] In a first aspect, the present invention also provides a method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), comprising: (a) determining the amount of at least two compounds having masses in grams / mole selected from the group consisting of Group 3, preferably Group 4, in a first body fluid sample of a subject; (b) analyzing the determined amounts of the at least two compounds using a computer-implemented predictive algorithm capable of predicting AD in a subject based on the at least two compounds, whereby, if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's dementia. The present invention relates to a method, comprising:

[0022] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), a first body fluid sample is obtained from the subject after the subject has been administered thiethylperazine or a pharmaceutically acceptable salt thereof, with the sample preferably being collected within 0.5 to 8 hours after administration of TEP.

[0023] In some preferred embodiments of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the computer-implemented predictive algorithm comprises: 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 further compound from group 3 or optionally in combination with at least one further compound from group 4, or 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 at least two compounds from group 3, preferably from group 4 The present invention uses a supervised machine learning algorithm that is trained with a training dataset that includes quantitative or qualitative data about the

[0024] As indicated above, whether a subject is afflicted with AD is determined according to current diagnostic criteria, preferably based on amyloid positron emission tomography and / or cerebrospinal fluid diagnostics and / or through cognitive testing.

[0025] The term "computer-implemented predictive algorithm" as used herein refers to a predictive algorithm automatically executed by a data processing device such as a computer. The data processing device preferably includes tangible rules for automatically executing the predictive algorithm based on the measurement results obtained by 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. Furthermore, the link can preferably be a direct wired link or a wireless link. A predictive algorithm, as referred to herein, is an algorithm that determines parameters related to the likelihood that a subject will suffer from AD. A predictive algorithm, as referred to herein, generates the aforementioned parameters, which can be further processed to establish a diagnosis result according to the method of the present invention. Preferably, the (computer-implemented predictive) parameters can be determined as described elsewhere herein. In some preferred embodiments of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), 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 trees classifier, extra-trees classifier, AdaBoost classifier, multi-layer perceptron classifier, gradient boosting classifier, Gaussian naive Bayes, K-nearest neighbor classifier, C-support vector classifier, quadratic discriminant analysis, and linear regression. In some preferred embodiments of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the supervised machine learning algorithm establishes and / or applies a logistic regression model, the logistic regression model being represented by equation (I): y=I+C1*F1+C2*F2+....+C n *F n (I) where I is the intercept and C n is the mass F n is the coefficient of Based on.

[0026] The computer-implemented prediction parameter is y in this specification. A positive y value indicates the possibility that the subject has or does not have AD, i.e., it is a prediction of the respective state. This is understood to be the case when training is based on the definition that AD diagnosis is a positive outcome, and therefore, the larger the absolute value, the more certain the prediction is, i.e., the larger the positive y value, the more likely the subject has AD, while the larger the negative absolute value of y, the more likely the subject does not have AD. On the other hand, when training is based on the definition that AD diagnosis is a negative outcome, the larger the negative y value, the more likely the subject has AD, while the larger the positive (absolute) value of y, the more likely the subject does not have AD.

[0027] Each coefficient preferably has a value in the range shown in Table 2 in the experimental section, each range excluding zero - see the associated row in Table 2, labeled "Range," for each specific mass combination. For example, for the mass combinations of 110.0367, 254.1153, 189.0096, and 224.084, respectively, in grams / mole, the intercept I has a value in the range of -50 to +50 excluding zero, the coefficient C1 of the first characteristic (i.e., mass = 110.0367 / grams / mole) is in the range of -150 to +150 excluding zero, etc. Furthermore, it is even more preferred if the coefficients of each mass have ratios to one another in the ranges shown below in Table A, more preferably shown below in Table B, and more preferably shown below in Table C, where these ratios more preferably apply for combinations of masses from Group 2, optionally in combination with masses of Group 4:

[0028] [Table 1]

[0029] [Table 2]

[0030] For each of Tables A, B, and C, "lower half" refers to the section below the diagonal line indicated by the " / / " symbols, and "upper half" refers to the section above that line.

[0031] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 189.0096 grams / mole, a compound having a mass of 224.084 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and analyzed in (b).

[0032] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 189.993 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.115 grams / mole are determined in (a) and analyzed in (b).

[0033] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in (a) and analyzed in (b).

[0034] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and analyzed in (b).

[0035] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 254.1153 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and analyzed in (b).

[0036] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in (a) and analyzed in (b).

[0037] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), at least the amounts of a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and analyzed in (b).

[0038] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and analyzed in (b).

[0039] In some preferred embodiments of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), at least the amounts of a compound having a mass of 175.0633 grams / mole and a compound having a mass of 208.0737 grams / mole are determined in (a) and analyzed in (b).

[0040] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 208.0737 grams / mole are determined in (a) and analyzed in (b).

[0041] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), at least the amounts of a compound having a mass of 208.0737 grams / mole and a compound having a mass of 702.5682 grams / mole are determined in (a) and analyzed in (b).

[0042] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and analyzed in (b).

[0043] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 254.1153 grams / mole, a compound having a mass of 189.9936 grams / mole, a compound having a mass of 189.0096 grams / mole, and a compound having a mass of 224.084 grams / mole are determined in (a) and analyzed in (b).

[0044] In some preferred embodiments of the methods for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 702.5682 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and analyzed in (b).

[0045] Second Aspect—Method for Identifying Subjects Suffering from or at Risk for Developing Alzheimer's Dementia (AD) (Change-Based Modeling) In a second aspect, the present invention provides a method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the method comprising: (a) In the first body fluid sample of the subject, the values ​​in grams / mole were: 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, 236.1049, 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); (b) determining the amount of the at least one compound in (a) in a second body fluid sample from the subject; (c) determining the change in the amount of the at least one compound determined according to (a) compared to the amount of each of the at least one compound determined according to (b); (d) analyzing the alterations determined in (c) using a computer-implemented predictive algorithm capable of predicting AD in the subject based on the at least one compound, whereby if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's dementia. wherein the first bodily fluid sample is obtained before administration of thiethylperazine or a pharmaceutically acceptable salt thereof, and the second bodily fluid sample is obtained after administration of thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0046] The definitions given above in the section relating to the first aspect also apply herein to the section relating to the second aspect of the invention.

[0047] Thiethylperazine (IUPAC: 2-(ethylsulfanyl)-10-[3-(4-methylpiperazin-1-yl)propyl]-10H-phenothiazine, CAS: 1420-55-9, TEP) has been shown to be effective in transporting amyloid beta (Abeta) from and through endothelial cells of the blood-brain barrier to the periphery in a mouse model of Alzheimer's disease (AD). It has also been shown that pharmaceutical activation of ABCC1 can reduce amyloid plaque deposition in the brain. The term "pharmaceutically acceptable," as used herein, refers to a salt that is pharmaceutically acceptable in the sense of not being harmful to the recipient and preferably being compatible with optional other ingredients of the formulation. Preferably, a pharmaceutically acceptable salt is a salt of thiethylperazine that causes at most a moderate adverse drug reaction, preferably at most a mild adverse drug reaction. As used herein, the term "mild" adverse reaction refers to an adverse reaction that does not require medical intervention, such as skin rash, headache, digestive problems, fatigue, etc., and a "moderate" adverse reaction is an adverse reaction that requires medical intervention but is not potentially life-threatening.Preferably, the pharmaceutically acceptable salt is selected from the group consisting of sulfate, pyrosulfate, bisulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, and succinate. , suberate ion, sebacate ion, fumarate ion, malate ion, maleate ion, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate ion, chlorobenzoate ion, methylbenzoate ion, dinitrobenzoate ion, hydroxybenzoate ion, methoxybenzoate ion, phthalate ion, terephthalate ion, sulfonate ion, xylenesulfonate ion, phenylacetate ion, phenylpropionate ion, phenylbutyrate ion, citrate ion, lactate ion, β -Hydroxybutyrate ion, glycolate ion, tartrate ion, methanesulfonate ion, propanesulfonate ion, naphthalene-1-sulfonate ion, naphthalene-2-sulfonate ion, almondate, adipate ion, alginate ion, mucate ion, aspartate ion, benzenesulfonate ion, butyrate ion, camphorate ion, camphorsulfonate ion, cyclopentanepropionate ion, digluconate ion, dodecylsulfate ion, ethanesulfonate The anions include one or more anions selected from the group consisting of phosphate, glucoheptanoate, glycerophosphate, hemisulfate, hexanoate, 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, picrate, pivalate, salicylate, thiocyanate, tosylate, arginate, and undecanoate.More preferably, the pharmaceutically acceptable salt comprises one or more anions selected from the group consisting of chloride, sulfate, mesylate, besylate, tosylate, fumarate, malonate, malate, maleate, succinate, lactate, glycolate, citrate, aspartate and mandelate, preferably malate and / or maleate, more preferably maleate.

[0048] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the at least one compound having a mass in grams / mole whose amount is determined in (a) and (b), whose change is determined in (c), and whose mass is 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).

[0049] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the at least one compound having a mass in grams / mole whose amount is determined in (a) and (b), whose change is determined in (c), and whose mass is analyzed in (d) is at least a compound having a mass in grams / mole of 110.0367.

[0050] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's Dementia (AD), 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) and (b), the changes are compared in (c) and analyzed in (d), and 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.

[0051] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least two compounds, preferably at least six compounds, or 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) and (b), the changes are compared in (c), and analyzed in (d), and 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.

[0052] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amount of at least one additional 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 from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4), is further determined in (a) and (b), and the changes are compared in (c) and analyzed in (d).

[0053] In some preferred embodiments of the method of identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD) of the second aspect, the method comprises: (a) determining the amount of at least two compounds having masses in grams / mole selected from the group consisting of Group 3, preferably Group 4, in a first body fluid sample of a subject; (b) determining the amount of the at least two compounds in (a) in a second body fluid sample from the subject; (c) determining the change in the amounts of the at least two compounds determined according to (a) compared to the amounts of each of the at least two compounds determined according to (b); (d) analyzing the alterations determined in (c) using a computer-implemented predictive algorithm capable of predicting AD in the subject based on the at least one compound, whereby if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's dementia. Includes:

[0054] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 189.0096 grams / mole, a compound having a mass of 224.084 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0055] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 189.993 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.115 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0056] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0057] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0058] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 254.1153 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and (b), changes are compared in (c), and analyzed in (d).

[0059] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0060] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0061] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0062] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole and a compound having a mass of 208.0737 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0063] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 208.0737 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0064] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), at least the amounts of a compound having a mass of 208.0737 grams / mole and a compound having a mass of 702.5682 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0065] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0066] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 254.1153 grams / mole, a compound having a mass of 189.9936 grams / mole, a compound having a mass of 189.0096 grams / mole, and a compound having a mass of 224.084 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0067] In some preferred embodiments of the method of the second aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 702.5682 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and (b), and changes are compared in (c) and analyzed in (d).

[0068] The determination of the amount in any one of steps (a) and / or (b) is carried out by mass spectrometry (MS), preferably by tandem mass spectrometry (MS / MS), more preferably by tandem mass spectrometry coupled with preceding liquid chromatography (LC-MS / MS), further details can be found in the section relating to the first aspect of the invention. The method is an in vitro method. The term "subject", as used herein, 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 cerebrospinal fluid 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 each independently selected from the group consisting of a blood sample, a urine sample, a cerebrospinal fluid sample (CSF), and a mixture of two or more thereof; preferably, the first body fluid sample and the second body fluid sample are the same type of sample, and both are selected from the group consisting of a blood sample, a urine sample, a cerebrospinal fluid sample (CSF), and a mixture of two or more thereof; more preferably, the first body fluid sample and the second body fluid sample are both blood samples (a first blood sample and a second blood sample), respectively.

[0069] Third Aspect - Method for Identifying Subjects Suffering from or at Risk for Developing Alzheimer's Dementia (AD) (Comparison of Pre- and Post-TEP Amounts) In a third aspect, the present invention provides a method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the method comprising: (a) In the first body fluid sample of the subject, the values ​​in grams / mole were: 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, 236.1049, 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); (b) determining the amount of the at least one compound in (a) in a second body fluid sample from the subject; (c) comparing the amount of the at least one compound determined according to (a) with the amount of each 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 disease for the subject or a risk of developing Alzheimer's disease for the subject. wherein the first bodily fluid sample is obtained before administration of thiethylperazine or a pharmaceutically acceptable salt thereof, and the second bodily fluid sample is obtained after administration of thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0070] The definitions given above in the section relating to the first aspect also apply herein 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 pharmaceutically acceptable salts thereof are also as defined above in the section relating to the second aspect.

[0071] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the 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).

[0072] In some preferred embodiments of the third aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the amount of a compound having a mass of at least 110.0367 grams / mole is determined in (a) and (b) and compared in (c).

[0073] In some preferred embodiments of the method of identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD) of the third aspect, 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 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) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject, and 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 of 110.0367 grams / mole.

[0074] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), amounts of at least two compounds, preferably at least six compounds, or 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 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) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject, and 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 of 110.0367 grams / mole.

[0075] In some preferred embodiments of the method of identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD) of the third aspect, the ATP is selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477, and 97.9769 (Group 3), more preferably from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4), in grams / mole. The amount of at least one additional compound having a mass determined in accordance with the formula (a) is further determined in the subject's first body fluid sample in steps (a) and (b) and compared in (c), wherein a change in the amount of the at least one compound according to (b) compared to the amount determined in (a), and a change in the amount of the at least one additional compound according to (b) compared to the amount determined in (a), is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0076] In some preferred embodiments of the method of identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD) of the third aspect, the method comprises: (a) determining the amount of at least two compounds having masses in grams / mole selected from the group consisting of Group 3, preferably Group 4, in a first body fluid sample of a subject; (b) determining the amount of the at least two compounds in (a) in a second body fluid sample from the subject; (c) comparing the amounts of the at least two compounds determined according to (a) with the amounts of each 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 disease for the subject or a risk of developing Alzheimer's disease for the subject. wherein the first bodily fluid sample is obtained prior to administration of thiethylperazine or a pharmaceutically acceptable salt thereof, and the second bodily fluid sample is obtained after administration of thiethylperazine or a pharmaceutically acceptable salt thereof to the subject.

[0077] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 189.0096 grams / mole, a compound having a mass of 224.084 grams / mole, and a compound having a mass of 254.1153 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0078] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 189.993 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.115 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0079] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0080] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 254.1153 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0081] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 254.1153 grams / mole, and a compound having a mass of 315.2409 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0082] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0083] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 315.2409 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0084] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 315.2409 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0085] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole and a compound having a mass of 208.0737 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0086] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 208.0737 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0087] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 208.0737 grams / mole and a compound having a mass of 702.5682 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0088] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 315.2409 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0089] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 254.1153 grams / mole, a compound having a mass of 189.9936 grams / mole, a compound having a mass of 189.0096 grams / mole, and a compound having a mass of 224.084 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0090] In some preferred embodiments of the method of the third aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 702.5682 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in a first body fluid sample from 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0091] The determination of the amount in any one of steps (a) and / or (b) is carried out by mass spectrometry (MS), preferably by tandem mass spectrometry (MS / MS), more preferably by tandem mass spectrometry coupled with preceding liquid chromatography (LC-MS / MS), further details can be found in the section relating to the first aspect of the invention. The method is an in vitro method. The term "subject", as used herein, 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 cerebrospinal fluid 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 each independently selected from the group consisting of a blood sample, a urine sample, a cerebrospinal fluid sample (CSF), and a mixture of two or more thereof; preferably, the first body fluid sample and the second body fluid sample are the same type of sample, and both are selected from the group consisting of a blood sample, a urine sample, a cerebrospinal fluid sample (CSF), and a mixture of two or more thereof; more preferably, the first body fluid sample and the second body fluid sample are both blood samples (a first blood sample and a second blood sample), respectively.

[0092] Fourth Aspect - Method for Identifying Subjects with Alzheimer's Disease (AD) (Comparison of Post-Administration Amount of TEP with Reference Value) A fourth aspect of the present invention is a method for identifying a subject suffering from Alzheimer's disease (AD), the method comprising: (a) In the subject body fluid samples, the concentrations in grams / mole were 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, 236.1049, 259.9982, 2 determining the amount of at least one compound having a mass selected from the group consisting of 85.1362, 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) 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 being 100%, is indicative of Alzheimer's dementia for the subject or indicates that the subject is at risk of developing Alzheimer's dementia. wherein the bodily fluid sample is obtained after administering thiethylperazine or a pharmaceutically acceptable salt thereof to a subject.

[0093] The definitions given in the section relating to the first aspect, and the explanations relating to thiethylperazine (TEP) and its pharmaceutically acceptable salts given in the second and third sections, also apply to the section relating to the fourth aspect of the invention herein.

[0094] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the 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).

[0095] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), in (a), the amount of at least a compound having a mass in grams / mole of 110.0367 is determined and compared in (b).

[0096] In some preferred embodiments relating to the method of the fourth aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), 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 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 at least five compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject, and 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.

[0097] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), 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 is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject, and 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.

[0098] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amount of at least one additional compound having a mass in grams / mol selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682, 161.0477, and 97.9769 (Group 3), more preferably from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 4), is determined in the subject's first body fluid sample in step (a) and 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 being 100%, is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0099] A fourth aspect of the present invention also provides a method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the method comprising: (a) determining the amount of at least two compounds having masses in grams / mole selected from the group consisting of Group 3, preferably Group 4, in a body fluid sample of a subject; (b) comparing the amounts of the at least two compounds determined according to (a) with 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 amount in healthy subjects being 100%, is indicative of Alzheimer's dementia for the subject or indicates that the subject is at risk of developing Alzheimer's dementia. wherein the body fluid sample is obtained after the subject has been administered thiethylperazine or a pharmaceutically acceptable salt thereof.

[0100] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 189.0096 grams / mole, a compound having a mass of 224.084 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0101] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 189.993 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.115 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0102] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0103] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0104] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 254.1153 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0105] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0106] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0107] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0108] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole and a compound having a mass of 208.0737 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0109] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 208.0737 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0110] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 208.0737 grams / mole and a compound having a mass of 702.5682 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 12% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0111] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0112] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 254.1153 grams / mole, a compound having a mass of 189.9936 grams / mole, a compound having a mass of 189.0096 grams / mole, and a compound having a mass of 224.084 grams / mole are determined in a first body fluid sample from the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0113] In some preferred embodiments relating to the fourth aspect of the method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 702.5682 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in a first body fluid sample from the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0114] In some preferred embodiments relating to the method of the fourth aspect for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), 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 the subject prior to administration of the TEP.

[0115] The determination of the amount in any one of steps (a) and / or (b) is carried out by mass spectrometry (MS), preferably by tandem mass spectrometry (MS / MS), more preferably by tandem mass spectrometry coupled with preceding liquid chromatography (LC-MS / MS), further details can be found in the section relating to the first aspect of the invention. The method is an in vitro method. The term "subject", as used herein, 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 cerebrospinal fluid 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 each independently selected from the group consisting of a blood sample, a urine sample, a cerebrospinal fluid sample (CSF), and a mixture of two or more thereof; preferably, the first body fluid sample and the second body fluid sample are the same type of sample, and both are selected from the group consisting of a blood sample, a urine sample, a cerebrospinal fluid sample (CSF), and a mixture of two or more thereof; more preferably, the first body fluid sample and the second body fluid sample are both blood samples (a first blood sample and a second blood sample), respectively.

[0116] Fifth Aspect—Second Diagnostic Use A fifth aspect of the present 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 one of the preferred embodiments described in the previous sections relating to the first, second, third or fourth aspects of the present invention, optionally in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3, preferably Group 4, for diagnosing AD in a subject or for determining the risk that a subject will develop AD.

[0117] Groups 1, 2, 3 and 4 are as defined above in the sections relating to the first, second, third or fourth aspects of the invention.

[0118] In some preferred embodiments of the at least one compound for use 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 described above in the section relating to the first, second, third or fourth aspect of the invention, 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 one 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 one 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 one of the preferred embodiments described above in the section relating to the first, second, third or fourth aspect of the invention, each 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.

[0119] In some preferred embodiments of the at least one compound for use 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 one of the preferred embodiments described above in the sections relating to the first, second, third or fourth aspects of the invention, 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 one of the preferred embodiments described above in the sections relating to the first, second, third or fourth aspects of the invention, 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 one of the preferred embodiments described above in the sections relating to the first, second, third or fourth aspects of the invention, each 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.

[0120] In some preferred embodiments of the at least one compound for use according to the fifth aspect, for diagnosing AD in a subject or determining the risk that a subject will develop AD, at least two compounds having a mass in grams / mole selected from the group consisting of Group 3 or Group 4.

[0121] Secondary diagnostic use (alternative expression) A fifth aspect of the present invention also relates to the 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 the preferred embodiments described above in the sections relating to the first, second, third or fourth aspects of the present invention, 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, in a sample of said subject, for diagnosing AD in a subject or for determining the risk of said subject to develop AD.

[0122] Groups 1, 2, 3 and 4 are as defined above in the sections relating to the first, second, third or fourth aspects of the invention.

[0123] In some preferred embodiments of the use according to the fifth aspect, at least two, preferably at least three, more preferably at least four, 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 one of the preferred embodiments described above in the sections relating to the first, second, third or fourth aspects of the invention, 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, in a sample from a subject, are used to diagnose AD in said subject or to determine said subject's risk of developing AD.

[0124] In some preferred embodiments of the use according to the fifth aspect, at least two, preferably at least six, 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 one of the preferred embodiments described above in the sections relating to the first, second, third or fourth aspects of the invention, 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, in a sample from a subject, are used to diagnose AD in said subject or to determine said subject's risk of developing AD.

[0125] In some preferred embodiments of the 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 in a sample of a subject for diagnosing AD in said subject or for determining said subject's risk for developing AD.

[0126] Sixth Aspect - Device A sixth aspect of the present invention provides a device adapted for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), comprising: (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; (b) a data processor employed to analyze the determined amount of at least one compound using a predictive algorithm implemented in the data processor, the predictive algorithm being capable of predicting AD in a subject based on at least two compounds, whereby, if AD is predicted, the subject suffering from AD is identified, or, if AD is predicted, the subject at risk of developing Alzheimer's dementia is identified. Including, relating to a device.

[0127] Preferred embodiments of the devices, especially those relating to compounds having particular masses in grams / mole and particular 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 aspects of the invention, and the definitions given above in these sections also apply to the sections relating to the devices herein.

[0128] Seventh Aspect - Kit In a seventh aspect, the present invention relates to a kit for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), comprising a reference sample of at least one compound having a mass in grams / mole selected from the group consisting of Group 1 or Group 2, optionally a reference sample of at least one compound having a mass in grams / mole selected from the group consisting of Group 3, or 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.

[0129] Preferred embodiments of the devices, especially those relating to compounds having particular masses in grams / mole and particular 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 aspects of the invention, and the definitions given above in these sections also apply to the sections relating to the devices herein.

[0130] The present invention is further exemplified by the following embodiments and combinations of embodiments, which are indicated by their respective dependencies and back references. In particular, it should be noted that in each case where a range of embodiments is mentioned, for example, in the context of a term such as "the process according to any one of embodiments 1 to 4," all embodiments within this range are intended to be expressly disclosed to those skilled in the art, that is, the expression of this term should be understood by those skilled in the art to be synonymous with "the process according to any one of embodiments 1, 2, 3, and 4."

[0131] 1. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the method comprising: (a) In the first body fluid sample of the subject, the values ​​in grams / mole were: 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, 236.1049, 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); (b) analyzing the determined amount of the at least one compound using a computer-implemented predictive algorithm capable of predicting AD in a subject based on the at least one compound, whereby, if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's dementia. wherein preferably the first body fluid sample is obtained from the subject after the subject has been administered thiethylperazine (TEP) or a pharmaceutically acceptable salt thereof, and the sample is preferably collected within 0.5 to 8 hours after the administration of TEP.

[0132] 2. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD) 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).

[0133] 3. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD) according to embodiment 1 or 2, wherein at least a compound having a mass in grams / mole of 110.0367 is determined in (a), and the determined amount is analyzed in (b).

[0134] 4. A method for identifying a subject suffering from Alzheimer's disease (AD) or at risk of developing Alzheimer's disease (AD), according to any one of embodiments 1 to 3, 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 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), more preferably one of the at least two compounds, preferably at least one of the three compounds, more preferably at least one of the four compounds, more preferably at least one of the five compounds is a compound having a mass in grams / mole of 110.0367.

[0135] 5. A method for identifying a subject suffering from Alzheimer's disease (AD) or at risk of developing Alzheimer's disease, according to any one of embodiments 1 to 4, wherein 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), and 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.

[0136] 6. A method for identifying a subject suffering from Alzheimer's disease (AD) or at risk of developing Alzheimer's disease, according to any one of embodiments 1 to 4, wherein the amount of at least one additional 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 further determined in the subject's first body fluid sample in step (a) and further analyzed in step (b).

[0137] 7. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), comprising: (a) determining the amount of at least two compounds having masses in grams / mole selected from the group consisting of Group 3, preferably Group 4, in a first body fluid sample of a subject; (b) analyzing the determined amounts of the at least two compounds using a computer-implemented predictive algorithm capable of predicting AD in a subject based on the at least two compounds, whereby, if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's dementia. A method comprising:

[0138] 8. The computer-implemented predictive algorithm detects the presence or absence of AD in body fluid samples from subjects known to have AD and subjects known not to have AD. 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 further compound from group 3 or optionally in combination with at least one further compound from group 4, or 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 at least two compounds from group 3, preferably from group 4 8. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD) according to any one of embodiments 1 to 7, wherein the method uses a supervised machine learning algorithm that has been trained with a training dataset comprising quantitative or qualitative data about:

[0139] 9. The method of 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 trees classifier, extra trees classifier, Adaboost classifier, multi-layer perceptron classifier, gradient boosting classifier, Gaussian naive Bayes, K-nearest neighbor classifier, C-support vector classifier, quadratic discriminant analysis, and linear regression.

[0140] 10. The supervised machine learning algorithm establishes and / or applies a logistic regression model, the logistic regression model being represented by equation (I): y=I+C1*F1+C2*F2+....+C n *F n (I) where I is the intercept and C n is the mass F n is the coefficient of 10. The method of embodiment 9, based on

[0141] 12. The method of any one of embodiments 1 to 10, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 189.0096 grams / mole, a compound having a mass of 224.084 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and analyzed in (b).

[0142] 13. The method of any one of embodiments 1 to 10, wherein at least the amounts of a compound having a mass of 189.993 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.115 grams / mole are determined in (a) and analyzed in (b).

[0143] 14. The method of any one of embodiments 1 to 10, wherein at least the amounts of a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in (a) and analyzed in (b).

[0144] 15. The method of any one of embodiments 1 to 10, wherein at least the amounts of a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and analyzed in (b).

[0145] 16. The method of any one of embodiments 1 to 10, wherein at least the amounts of a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 254.1153 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and analyzed in (b).

[0146] 17. The method of any one of embodiments 1 to 10, wherein at least the amounts of a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in (a) and analyzed in (b).

[0147] 18. The method of any one of embodiments 1 to 10, wherein at least the amounts of a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and analyzed in (b).

[0148] 19. The method of any one of embodiments 1 to 10, wherein at least the amounts of a compound having a mass of 110.0367 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and analyzed in (b).

[0149] 20. The method of any one of embodiments 1 to 10, wherein at least the amount of a compound having a mass of 175.0633 grams / mole and a compound having a mass of 208.0737 grams / mole is determined in (a) and analyzed in (b).

[0150] 21. The method of any one of embodiments 1 to 10, wherein at least the amounts of a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 208.0737 grams / mole are determined in (a) and analyzed in (b).

[0151] 22. The method of any one of embodiments 1 to 10, wherein at least the amount of a compound having a mass of 208.0737 grams / mole and a compound having a mass of 702.5682 grams / mole is determined in (a) and analyzed in (b).

[0152] 23. The method of any one of embodiments 1 to 10, wherein at least the amounts of a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and analyzed in (b).

[0153] 24. The method of any one of embodiments 1 to 10, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 254.1153 grams / mole, a compound having a mass of 189.9936 grams / mole, a compound having a mass of 189.0096 grams / mole, and a compound having a mass of 224.084 grams / mole are determined in (a) and analyzed in (b).

[0154] 25. The method of any one of embodiments 1 to 10, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 702.5682 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and analyzed in (b).

[0155] 25. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the method comprising: (a) In the first body fluid sample of the subject, the values ​​in grams / mole were: 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, 236.1049, 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); (b) determining the amount of the at least one compound in (a) in a second body fluid sample from the subject; (c) determining the change in the amount of the at least one compound determined according to (a) compared to the amount of each of the at least one compound determined according to (b); (d) analyzing the alterations determined in (c) using a computer-implemented predictive algorithm capable of predicting AD in the subject based on the at least one compound, whereby if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's dementia. wherein the first bodily fluid sample is obtained prior to administration of thiethylperazine or a pharmaceutically acceptable salt thereof, and the second bodily fluid sample is obtained after thiethylperazine or a pharmaceutically acceptable salt thereof has been administered to the subject.

[0156] 26. The method of embodiment 25, wherein the at least one compound having a mass in grams / mole, the amount of which is determined in (a) and (b), the change of which is determined in (c), and which is 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).

[0157] 27. The method of embodiment 25 or 26, wherein the at least one compound having a mass in grams / mole, the amount of which is determined in (a) and (b), the change of which is determined in (c), and which is analyzed in (c), is at least a compound having a mass in grams / mole of 110.0367.

[0158] 28. The method of any one of embodiments 25-27, 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 grams / mole selected from the group consisting of Group 1 or Group 2 are determined in (a) and (b), the changes are compared in (c), and analyzed in (d), and 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.

[0159] 29. The method of any one of embodiments 25-28, wherein the amounts of at least two compounds, preferably at least six compounds, or 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) and (b), the changes are compared in (c), and analyzed in (d), and 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.

[0160] 30. The method of any one of embodiments 25 to 29, wherein the amount of at least one additional 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 208.0737, 315.2409, 175.0633, 702.5682 (Group 4), is further determined in (a) and (b), the change is compared in (c), and analyzed in (d).

[0161] 31. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), comprising: (a) determining the amount of at least two compounds having masses in grams / mole selected from the group consisting of Group 3, preferably Group 4, in a first body fluid sample of a subject; (b) determining the amount of the at least two compounds in (a) in a second body fluid sample from the subject; (c) determining the change in the amounts of the at least two compounds determined according to (a) compared to the amounts of each of the at least two compounds determined according to (b); (d) analyzing the alterations determined in (c) using a computer-implemented predictive algorithm capable of predicting AD in the subject based on the at least one compound, whereby if AD is predicted, the subject is identified as suffering from AD or at risk of developing Alzheimer's dementia. A method comprising:

[0162] 32. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 189.0096 grams / mole, a compound having a mass of 224.084 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0163] 33. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 189.993 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.115 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0164] 34. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0165] 35. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0166] 36. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 254.1153 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0167] 37. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0168] 38. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0169] 39. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0170] 40. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole and a compound having a mass of 208.0737 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0171] 41. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 208.0737 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0172] 42. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 208.0737 grams / mole and a compound having a mass of 702.5682 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0173] 43. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0174] 44. The method of any one of embodiments 25 to 30, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 254.1153 grams / mole, a compound having a mass of 189.9936 grams / mole, a compound having a mass of 189.0096 grams / mole, and a compound having a mass of 224.084 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0175] 45. The method of any one of embodiments 25-30, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 702.5682 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in (a) and (b), and the changes are compared in (c), and analyzed in (d).

[0176] 46. ​​A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the method comprising: (a) In the first body fluid sample of the subject, the values ​​in grams / mole were: 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, 236.1049, 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); (b) determining the amount of the at least one compound in (a) in a second body fluid sample from the subject; (c) comparing the amount of the at least one compound determined according to (a) with the amount of each 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 disease for the subject or a risk of developing Alzheimer's disease for the subject. wherein the first bodily fluid sample is obtained prior to administration of thiethylperazine or a pharmaceutically acceptable salt thereof, and the second bodily fluid sample is obtained after thiethylperazine or a pharmaceutically acceptable salt thereof has been administered to the subject.

[0177] 47. A method for identifying a subject suffering from Alzheimer's disease (AD) or at risk of developing Alzheimer's disease, 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).

[0178] 48. A method for identifying a subject suffering from Alzheimer's disease (AD) or at risk of developing Alzheimer's disease, as described in embodiment 46 or 47, wherein in (a) and (b), the amount of a compound having a mass of at least 110.0367 grams / mol is determined and compared in (c).

[0179] 49. A method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46-48, 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 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 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) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject, and 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 of 110.0367 grams / mole.

[0180] 50. A method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 49, wherein the amounts of at least two compounds, preferably at least six compounds, or 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 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) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject, and 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 of 110.0367 grams / mole.

[0181] 51. The amount of at least one additional 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), is further determined in the subject's first body fluid sample in steps (a) and (b) and compared in (c), and the amount of at least one additional compound having a mass in grams / mole selected from the group consisting of 208.0737, 315.2409, 175.0633, 702.5682 (Group 5) is further determined in the subject's first body fluid sample in steps (a) and (b), and compared in (c), 51. The method of identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD) according to any one of embodiments 46 to 50, wherein a change in the amount of the at least one compound compared to the amount determined in (a), and a change in the amount of the at least one additional compound according to (b) compared to the amount determined in (a), is indicative of Alzheimer's dementia for the subject or a risk for the subject of developing Alzheimer's dementia.

[0182] 52. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the method comprising: (a) determining in a first body fluid sample of a subject the amount of at least two compounds having masses in grams / mole selected from the group consisting of Group 3; (b) determining the amount of the at least two compounds in (a) in a second body fluid sample from the subject; (c) comparing the amounts of the at least two compounds determined according to (a) with the amounts of each 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 disease for the subject or a risk of developing Alzheimer's disease for the subject. wherein the first bodily fluid sample is obtained prior to administration of thiethylperazine or a pharmaceutically acceptable salt thereof, and the second bodily fluid sample is obtained after thiethylperazine or a pharmaceutically acceptable salt thereof has been administered to the subject.

[0183] 53. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 189.0096 grams / mole, a compound having a mass of 224.084 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and a change of at least 1% in the amount of each of these compounds in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0184] 54. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 189.993 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.115 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and a change of at least 1% in the amount of each of these compounds in (b) compared to the amount determined in (a) indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0185] 55. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0186] 56. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and a change of at least 12.5% ​​in the amount of each of these compounds in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0187] 57. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 254.1153 grams / mole, and a compound having a mass of 315.2409 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0188] 58. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and a change of at least 12.5% ​​in the amount of each of these compounds in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0189] 59. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and a change of at least 2% in the amount of each of these compounds in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0190] 60. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and a change of at least 1% in the amount of each of these compounds in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0191] 61. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole and a compound having a mass of 208.0737 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and a change of at least 12.5% ​​in the amount of each of these compounds in (b) compared to the amount determined in (a) indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0192] 62. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 208.0737 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and a change of at least 1% in the amount of each of these compounds in (b) compared to the amount determined in (a) indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0193] 63. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 208.0737 grams / mole and a compound having a mass of 702.5682 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and wherein a change of at least 1% in the amount of each of these compounds in (b) compared to the amount determined in (a) indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0194] 64. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in steps (a) and (b) and compared in (c), and a change of at least 40% in the amount of each of these compounds in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0195] 65. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 46 to 51, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 254.1153 grams / mole, a compound having a mass of 189.9936 grams / mole, a compound having a mass of 189.0096 grams / mole, and a compound having a mass of 224.084 grams / 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 in (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0196] 66. 52. The method of any one of embodiments 46-51, wherein the amounts of at least a compound having a mass of 110.0367 g / mole, 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 702.5682 g / mole, a compound having a mass of 208.0737 g / mole, a compound having a mass of 315.2409 g / mole, a compound having a mass of 232.004 g / mole, and a compound having 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 2% in the amount of each of these compounds according to (b) compared to the amount determined in (a) is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0197] 67. A method for identifying a subject suffering from Alzheimer's disease (AD), the method comprising: (a) In the subject body fluid samples, the concentrations in grams / mole were 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, 236.1049, 259.9982, 2 determining the amount of at least one compound having a mass selected from the group consisting of 85.1362, 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) 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 being 100%, is indicative of Alzheimer's dementia for the subject or indicates that the subject is at risk of developing Alzheimer's dementia. wherein the bodily fluid sample is obtained after the subject has been administered thiethylperazine or a pharmaceutically acceptable salt thereof.

[0198] 68. A method for identifying a subject suffering from Alzheimer's disease (AD) or at risk of developing Alzheimer's disease, 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).

[0199] 69. A method for identifying a subject suffering from Alzheimer's disease (AD) or at risk of developing Alzheimer's disease, as described in embodiment 67 or 68, wherein in (a) and (b), at least the amount of a compound having a mass in grams / mol of 110.0367 is determined and compared in (c).

[0200] 70. A method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67-69, 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 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), and 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 at least five compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject, and 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.

[0201] 71. A method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 70, wherein 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), and 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, is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject, and 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.

[0202] 72. The amount of at least one additional 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, and 702.5682 (Group 4), is determined in the subject's first body fluid sample in steps (a) and (b) and compared in (c), and the amount of the at least one compound in (b) is compared in (a). 72. A method for identifying a subject suffering from Alzheimer's dementia (AD) or at risk of developing Alzheimer's dementia (AD) according to any one of embodiments 67 to 71, wherein a change compared to the determined amount and a change in the amount of the at least one further 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 being 100%, is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0203] 73. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD), the method comprising: (a) determining the amount of at least two compounds having masses in grams / mole selected from the group consisting of Group 3, preferably Group 4, in a body fluid sample of a subject; (b) comparing the amounts of the at least two compounds determined according to (a) with 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 amount in healthy subjects being 100%, is indicative of Alzheimer's dementia for the subject or indicates that the subject is at risk of developing Alzheimer's dementia. wherein the bodily fluid sample is obtained after the subject has been administered thiethylperazine or a pharmaceutically acceptable salt thereof.

[0204] 74. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 189.0096 grams / mole, a compound having a mass of 224.084 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amount of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0205] 75. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 189.993 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.115 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amount of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0206] 76. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amount of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0207] 77. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0208] 78. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 224.084 grams / mole, a compound having a mass of 254.1153 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amount of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0209] 79. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, and a compound having a mass of 702.5682 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amount of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0210] 80. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0211] 81. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amount of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0212] 82. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole and a compound having a mass of 208.0737 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0213] 83. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 208.0737 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amount of each of these compounds indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0214] 84. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 208.0737 grams / mole and a compound having a mass of 702.5682 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 12% in the amounts of each of these compounds indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0215] 85. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 175.0633 grams / mole, a compound having a mass of 208.0737 grams / mole, and a compound having a mass of 315.2409 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds indicates Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0216] 86. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 232.004 grams / mole, a compound having a mass of 254.1153 grams / mole, a compound having a mass of 189.9936 grams / mole, a compound having a mass of 189.0096 grams / mole, and a compound having a mass of 224.084 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amount of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0217] 87. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD) according to any one of embodiments 67 to 72, wherein the amounts of at least a compound having a mass of 110.0367 grams / mole, a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, a compound having a mass of 702.5682 grams / mole, a compound having a mass of 208.0737 grams / mole, a compound having a mass of 315.2409 grams / mole, a compound having a mass of 232.004 grams / mole, and a compound having a mass of 254.1153 grams / mole are determined in a first body fluid sample of the subject in step (a) and compared in (b), and a change of at least 3% in the amounts of each of these compounds is indicative of Alzheimer's dementia for the subject or a risk of developing Alzheimer's dementia for the subject.

[0218] 88. A method for identifying a subject suffering from Alzheimer's disease (AD) or at risk of developing Alzheimer's disease, according to any one of embodiments 67 to 72, wherein the average amount of values ​​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 the subject before administration of TEP.

[0219] 89. The method of any one of embodiments 1 to 88, wherein the determination of the amount in any one of steps (a) and / or (b) is carried out by mass spectrometry (MS), preferably by tandem mass spectrometry (MS / MS), more preferably by tandem mass spectrometry combined with preceding liquid chromatography (LC-MS / MS).

[0220] 90. A method according to any one of embodiments 1 to 89, which is an in vitro method.

[0221] 91. The method of any one of embodiments 1 to 90, wherein the subject is a human.

[0222] 92. The method of 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 cerebrospinal fluid 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 each independently selected from the group consisting of a blood sample, a urine sample, a cerebrospinal fluid sample (CSF), and a mixture of two or more thereof, preferably, the first body fluid sample and the second body fluid sample are the same type of sample, both selected from the group consisting of a blood sample, a urine sample, a cerebrospinal fluid sample (CSF), and a mixture of two or more thereof, more preferably, the first body fluid sample and the second body fluid sample are both blood samples (a first blood sample and a second blood sample), respectively.

[0223] 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 1-92, optionally in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3, preferably Group 4, for diagnosing AD in a subject or determining the risk that a subject will develop AD.

[0224] 94. 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 one of embodiments 1 to 92, 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 one of embodiments 1 to 92, 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 one of embodiments 1 to 92, 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 one of embodiments 1 to 92, At least one compound for use according to embodiment 93, optionally used in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4, each.

[0225] 95. 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 one of embodiments 1 to 92, 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 one of embodiments 1 to 92, 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 one of embodiments 1 to 92, At least one compound for use according to embodiment 93, optionally used in combination with at least one compound having a mass in grams / mole selected from the group consisting of Group 3 or Group 4, each.

[0226] 96. At least two compounds having a mass in grams / mole selected from the group consisting of Group 3 or Group 4 for diagnosing AD in a subject or determining the risk of a subject developing AD.

[0227] Secondary diagnostic use (alternative expression) 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 1-92, 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, in a sample of said subject, for diagnosing AD in a subject or determining the risk of said subject to develop AD.

[0228] 98. The use according to embodiment 97, wherein at least two, preferably at least three, more preferably at least four, 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 one of embodiments 1 to 93, 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, in a sample of a subject, are used to diagnose AD in said subject or to determine said subject's risk of developing AD.

[0229] 99. The use according to embodiment 97, wherein at least two, preferably at least six, 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 one of embodiments 1 to 92, 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, in a sample of a subject, are used to diagnose AD in said subject or to determine said subject's risk of developing AD.

[0230] 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 determining the risk of the subject developing AD.

[0231] 101. A device adapted for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), comprising: (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; (b) a data processor employed to analyze the determined amount of at least one compound using a predictive algorithm implemented in the data processor, the predictive algorithm being capable of predicting AD in a subject based on at least two compounds, whereby, if AD is predicted, the subject suffering from AD is identified, or, if AD is predicted, the subject at risk of developing Alzheimer's dementia is identified. Including, the device.

[0232] 102. A kit for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), comprising a reference sample of at least one compound having a mass in grams / mole selected from the group consisting of Group 1 or Group 2, optionally a reference sample of at least one compound having a mass in grams / mole selected from the group consisting of Group 3, or 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. [Example]

[0233] The present invention will be further illustrated by the following Reference Examples, Comparative Examples and Examples.

[0234] Example The following examples are intended to be merely illustrative of the present invention and are not to be construed in any way as limiting the scope of the present invention.

[0235] I method I.1 Treatment Fifteen human subjects (seven healthy and eight with Alzheimer's disease) were treated with 6.5 mg of thiethylperazine (TEP). Blood samples were collected at 0, 0.5, 1, 1.5, 2, 4, and 8 hours after administration. AD subjects were classified by Mini-Mental State Examination (MMSE) scores ranging from 25 to 18. The diagnosis of AD was further confirmed by the tests recommended according to the German DGN / DGPPN S3 guideline "Dementia" and by the following: - Psychometric and cognitive testing - Lumbar puncture in subjects with an uncertain AD diagnosis after CNS imaging - Clinical Dementia Rating (global CDR) of 0.5 or 1 and a memory box score of at least 0.5. - Isolated or predominant episodic memory impairment, manifested by memory performance on the Logical Memory subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale-III that is one standard deviation below age-adjusted norms.

[0236] I.2 Blood Sampling A 10 ml sample of venous blood was collected in a standardized test tube containing EDTA and gently shaken once or twice. As soon as possible (within a maximum of 30 minutes), the sample was centrifuged at 1600 g for 10 minutes at room temperature. The plasma was aliquoted into six 0.5 ml portions. All aliquots were frozen in a deep freezer (-80°C) within 10 minutes of centrifugation and stored until use.

[0237] I.3 Untargeted metabolomics All procedures performed in this section were performed by BGI Genomics. Untargeted 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).

[0238] 1. Main equipment and reagents Ultra-high performance liquid chromatography: Waters 2D UPLC, Waters, USA High-resolution mass spectrometer: Q Exactive, Thermo Fisher Scientific, USA Chromatography column: ACQUITY UPLC BEH C18 1.7 μm, 2.1*100 mm, Waters, USA Low-temperature high-speed centrifuge: Centrifuge 5430, Eppendorf Vortex: QL-901, Kylin-bell Lab Instruments Co., Ltd., China Ultrapure water system: Milli-Q Integral, Millipore Corporation, USA Vacuum concentrator: Maxi Vacbeta, GENE COMPANY The internal standard mix (IS) contains: L-leucine-d3, L-phenylalanine (13C9, 99%), L-tryptophan-d5, and progesterone-2,3,4-13C3. MS-grade methanol (A454-4) and acetonitrile (A996-4) were purchased from Thermo Fisher Scientific (USA). Formic acid was purchased from DIMKA (50144-50ml, USA), and ammonium formate (17843-250G, Honeywell Fluka, USA) was obtained from Fluka. Ultrapure water was filtered through a Milli-Q system.

[0239] 2. Extraction of Metabolites Metabolite extraction was primarily performed according to previously reported methods [4][5]. Briefly, 100 μL of plasma sample was extracted by directly adding 300 μL of pre-chilled methanol and acetonitrile (2:1, v / v). Internal standard mix 1 (IS1) and internal standard mix 2 (IS2) were added for sample preparation quality control. After vortexing for 1 min and incubation at -20°C for 2 h, the sample was centrifuged at 4000 rpm for 20 min, and the supernatant was then transferred for vacuum lyophilization. Metabolites were resuspended in 150 μL of 50% methanol, centrifuged at 4000 rpm for 30 min, and the supernatant was transferred to an autosampler vial for LC-MS analysis. To assess the reproducibility of the overall LC-MS analysis, quality control (QC) samples were prepared by pooling the same volume of each sample.

[0240] 3 LC-MS / MS analysis 3.1. Chromatography conditions Samples were analyzed on a Waters 2D UPLC (Waters, USA) coupled to a Q-Exactive mass spectrometer (Thermo Fisher Scientific, USA) equipped 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), with the column temperature maintained at 45 °C. The mobile phase consisted of 0.1% formic acid (A) and acetonitrile (B) in positive mode, and 10 mM ammonium formate (A) and acetonitrile (B) in negative mode. The 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–2% B; and 12.1–15 min, 2% B. The flow rate was 0.35 mL / min, and the injection volume was 5 μL.

[0241] 3.2 Mass spectrometry conditions Mass spectrometric settings for positive / negative ionization mode were as follows: spray voltage: 3.8 / -3.2 kV; sheath gas flow rate: 40 arbitrary units (arb); auxiliary gas flow rate: 10 arb; auxiliary gas heater temperature: 350 °C; capillary temperature: 320 °C. The full scan range was 70-1050 m / z, with a resolution of 70,000. The automatic gain control (AGC) target for MS acquisition was set to 3e6, and the maximum ion injection time was 100 ms. The top three precursors were selected for subsequent MSMS fragmentation using a maximum ion injection time of 50 ms and a resolution of 17,500, with an AGC of 1e5. The stepwise normalized collision energies were set to 20, 40, and 60 eV.

[0242] To provide more reliable experimental results during instrument testing, samples were randomly ordered to reduce systematic errors. QC samples were interspersed with every 10 samples.

[0243] 4. Data Preprocessing The raw mass spectrometry data (raw files) collected by LC-MS / MS, including peak extraction, intra- and inter-group retention time correction, adduct ion pooling, missing value imputation, background peak labeling, and metabolite identification, were imported into Compound Discoverer 3.1 (Thermo Fisher Scientific, USA) for data processing. Finally, information on compound molecular weights, retention times, peak areas, and identification results was exported. Metabolite identification was the result of a combination of the standard library built by BGI, mzCloud, and ChemSpider (HMDB, KEGG, LipidMaps) databases.

[0244] The results of Compound Discoverer 3.1 export are imported into metaX for data preprocessing, including: 1. Normalizing the data using Probabilistic Exponential Normalization (PQN[6]) to obtain relative peak areas; 2. Correcting batch effects using QC-RLSC[4] (Robust Loess Signal Correction Based on Quality Control); 3. Calculating the CV (Coefficient of Variation) of relative peak areas across all QC samples and removing compounds with CVs greater than 30%. Probabilistic Exponential Normalization (PQN): Probabilistic Exponential Normalization is the calculation of the average of all QC samples for each feature to obtain a reference vector; calculating the median between the reference vector and each sample to obtain a coefficient vector associated with each sample, and then normalization was performed by dividing each sample by the median of the coefficient vector (each sample has a different median).

[0245] QC-RLSC [4]: ​​Local polynomial regression fitting signal correction based on QC sample information (QC-RLSC).

[0246] Data quality was assessed by repeatability of QC sample detection, including chromatogram overlap, PCA, peak number, and peak response intensity difference of QC samples.

[0247] 5 Partial Least Squares-Discriminant Analysis (PLS-DA) A partial least squares regression method was used to establish a relationship model between metabolite expression and sample category, and modeling prediction of sample category was achieved. After log2-log transformation of the data, a PLS-DA model between the comparison groups (two groups) was established, and Par scaling was used. Seven-fold cross-validation was performed during modeling. To evaluate the model, the PLS-DA model [7][8] was subjected to 200 response permutations.

[0248] The data were used for fold change analysis and T-test. Fold change (FC) was obtained through fold change analysis, p-value was obtained through Student's T-test, and p-value was corrected for false discovery rate (FDR) to obtain q-value.

[0249] Comparisons were made between healthy subjects before administration of thiethylperazine versus subjects with Alzheimer's disease before administration of thiethylperazine, and healthy subjects after administration of thiethylperazine versus subjects with Alzheimer's disease after administration of thiethylperazine.

[0250] 6 Database and Identification The databases used for compound identification included mzCloud, Chemspider, Human Metabolome Database (HMDB), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Lipidmaps database.

[0251] II. Identification of metabolites / masses of diagnostic value 1. Software Python 3.9.5 running in Spyder 5.3.2 IDE with libraries: scikit-learn, pandas, and numpy. Windows 11, Microsoft Excel 365.

[0252] 2. Data Processing and Filtering After processing all blood samples using the untargeted metabolomics procedure, the area under the curve (AUC) values ​​for all masses (x) were calculated using the formula z=(xu) / s where u was the mean of all samples and s was the standard deviation of all samples. The normalized data represents data set 1.

[0253] A correlation analysis of all masses in Dataset 1 was then performed. If an absolute pairwise correlation of greater than 0.95 was found, one mass in the pair was excluded from further analysis. The remaining data represent Dataset 2.

[0254] Dataset 2 was then successively filtered for (i) masses that were not significantly different between healthy and AD subjects at the pre-TEP time point and (ii) masses that were significantly different at the post-TEP time point according to Student's T-test after performing PLS-DA to generate dataset 3.

[0255] Dataset 3 was then checked for masses found to have highly correlated masses in Dataset 1. Four such masses were identified, and the correlated masses excluded from Dataset 2 were reintroduced into Dataset 3, resulting in a final dataset containing 45 masses.

[0256] 3. Analysis of predicted values ​​of single masses For better visualization, the AUC data at 2 hours after TEP administration for each of the 45 selected masses were normalized to the respective mean of healthy individuals (X mass i =AUC mass i *100 / average all Healthy mass i ). Thirty-two masses were significantly different in samples obtained from AD subjects than in samples from healthy subjects. For 42 of the 45 masses, an absolute change of 3% (compared to the mean of healthy subjects) was sufficient to diagnose AD with at least 67% accuracy (Table 1).

[0257] [Table 3] TIFF2025537481000004.tif253154TIFF2025537481000005.tif253154TIFF2025537481000006.tif253154TIFF2025537481000007.tif143154

[0258] 4. Screening for mass combinations that predict disease state To increase 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 seven masses (excluding combinations that may contain highly correlated masses) and extract combinations with high diagnostic value. Due to the small cohort size, a rigorous approach to training and testing classifier models was used to estimate the diagnostic robustness of specific mass combinations for unknown samples.

[0259] We used a scikit-learn GridSearch pipeline with a nested cross-validation approach to evaluate the best combination of masses and classifiers for identifying AD patients. Within the GridSearch pipeline, we screened the following supervised learning methods: logistic regression, stochastic gradient descent classifier (SGD classifier), decision tree classifier, random trees classifier, extratrees classifier, Adaboost classifier, multilayer perceptron classifier (MLP classifier), gradient boosting classifier, Gaussian Naive Bayes (Gaussian NB), K-nearest neighbor classifier, C-support vector classifier (SVC), quadratic discriminant analysis, and linear regression. For each method, hyperparameter optimization and training were performed on 70% of the complete dataset using a stratified 3-fold data split (inner loop). The classifier with the highest area under the ROC curve (AUC) was then evaluated on the remaining 30% of the dataset using a leave-one-out method (outer loop) to assess the generalizability and accuracy of the model and mass combination.

[0260] result Screening revealed numerous combinations of 1 to 7 of the 45 masses found that were most beneficial for accurately predicting disease status. Table 2 below shows an exemplary selection of mass combinations that predicted disease status with high accuracy. Because the predictions of most classifiers were difficult to calculate or could not be predicted at all, only the logistic regression algorithm was selected for this Table 2. However, in most cases, the decisive factor for accurate prediction was the combination of masses, not the algorithm used for prediction, which again emphasizes the validity of the selected masses. This fact is illustrated in Table 4, which shows the main diagnostic parameters for different classifiers using the same mass combination.

[0261] For disease prognosis, the logistic regression equation would be interpreted as follows: y=I+C1*F1+C2*F2+...+C n *F n where I is the intercept and C n is the mass F n [The coefficient of y is the coefficient of y. Positive y values ​​are predictive of Alzheimer's disease, while negative values ​​predict a non-disease state. The larger the absolute value, the more certain the prediction.

[0262] For example, for the first combination of masses shown in Table 2, the formula was: y=19,61932517+(-64,96994161*[Feat1])+(43,45875272*[Feat2])+(-60,67815063*[Feat3])+(47,81007498*[Feat4]) [where [FeatX] was the concentration (standard scale or absolute value) of each mass in the sample].

[0263] [Table 4] TIFF2025537481000009.tif25382

[0264] Without being bound by this theory, of the 45 compounds represented by the mass in grams / mole above, the following five compounds are believed to be related to the compounds listed below in Table 3:

[0265] [Table 5]

[0266] [Table 6] TIFF2025537481000012.tif236147

[0267] References [1] US 2015 / 0374711 A1 [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 [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, Volume 8, Issue 5, e63644 [4] Dunn W B, 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 [5] Sarafian M H, Gaudin M, Lewis M R, 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 [6] Guida R D, Engel J, Allwood J W, et al. Non-targeted UHPLC-MS metabolomic data processing methods: a comparative investigation of normalisation, missing value imputation, transformation and scaling[J]. Metabolomics, 2016, 12(5):93 [7] Barker, M.; Rayens, W., Partial least squares for discrimination. J Chemometr 2003, 17(3):166-173 [8] Westerhuis JA, Hoefsloot HCJ, Smit S, et al. Assessment of PLSDA cross validation[J]. Metabolomics, 2008, 4(1):81-89

Claims

1. 1. 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 body fluid sample of a subject the amount of at least a compound having a mass in grams / mole of 110.0367; (b) determining the amount of the same compound as in (a) in a second body fluid sample from the subject; (c) determining the change in the amount of the compound determined according to (a) compared to the amount of each compound determined according to (b); (d) analyzing the changes determined in (c) using a computer-implemented predictive algorithm capable of predicting AD in the subject based on the compound, whereby if AD is predicted, the subject is identified as having AD or at risk of developing Alzheimer's dementia. wherein the first bodily fluid sample is obtained prior to administration of thiethylperazine or a pharmaceutically acceptable salt thereof, and the second bodily fluid sample is obtained after thiethylperazine or a pharmaceutically acceptable salt thereof has been administered to the subject.

2. 2. The method of claim 1, wherein the first body fluid sample is obtained from the subject after the subject has been administered thiethylperazine or a pharmaceutically acceptable salt thereof.

3. 3. The method of claim 1 or 2, wherein the amount of at least one additional compound having a mass in grams / mol selected from the group consisting of 208.0737, 315.2409, 175.0633, and 702.5682 (Group 4) is further determined in the subject's first body fluid sample in step (a) and further analyzed in step (b).

4. The computer-implemented predictive algorithm is used to measure the presence or absence of AD in body fluid samples from subjects known to have AD and subjects known not to have AD. A compound having a mass in grams / mole of 110.0367, optionally in combination with at least one further compound from group 4.

4. A method for identifying a subject suffering from or at risk of developing Alzheimer's disease (AD) according to any one of claims 1 to 3, using a supervised machine learning algorithm trained with a training dataset comprising quantitative or qualitative data about:

5. 5. The method of claim 1, wherein at least the amounts of a compound having a mass of 110.0367 grams / mole, a compound having a mass of 175.0633 grams / mole, and a compound having a mass of 208.0737 grams / mole are determined in (a) and analyzed in (b).

6. 1. A method for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), the method comprising: (a) determining the amount of a compound having a mass in grams / mole of 110.0367 in a first body fluid sample of a subject; (b) determining the amount of the same compound as in (a) in a second body fluid sample from the subject; (c) comparing the amount of the compound determined according to (a) with the amount of each 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 disease for the subject or a risk of developing Alzheimer's disease for the subject. wherein the first bodily fluid sample is obtained prior to administration of thiethylperazine or a pharmaceutically acceptable salt thereof, and the second bodily fluid sample is obtained after thiethylperazine or a pharmaceutically acceptable salt thereof has been administered to the subject.

7. 1. A method for identifying a subject suffering from Alzheimer's disease (AD), the method comprising: (a) determining the amount of a compound having a mass in grams / mole of 110.0367 in a sample of a subject's body fluid; (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 being 100%, is indicative of Alzheimer's dementia for the subject or indicates that the subject is at risk of developing Alzheimer's dementia; wherein the bodily fluid sample is obtained after the subject has been administered thiethylperazine or a pharmaceutically acceptable salt thereof.

8. A compound having a mass in grams / mole of 110.0367, optionally in combination with at least one compound having a mass in grams / mole selected from Group 4, for diagnosing AD in a subject or determining the risk that a subject will develop AD.

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

10. 1. A device adapted for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), comprising: (a) an analytical unit capable of determining the amount of at least one compound having a mass in grams / mole of 110.0367 in a first body fluid sample of a subject; (b) a data processor employed to analyze the determined amounts of the compounds using a predictive algorithm implemented in the data processor that is capable of predicting AD in a subject based on at least two compounds, whereby, if AD is predicted, a subject suffering from AD is identified, or if AD is predicted, a subject at risk of developing Alzheimer's dementia is identified. Including, the device.

11. 1. A kit for identifying a subject suffering from or at risk of developing Alzheimer's dementia (AD), comprising: a reference sample of a compound having a mass in grams / mole of 110.0367; 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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