p53 POST-TRANSLATIONAL MODIFICATIONS AS MARKERS IN THE DIAGNOSIS AND PROGNOSIS OF A NEURODEGENERATIVE DISEASE

A method for diagnosis or prognosis of Alzheimer's disease (AD) in a subject, said method comprising:

• identifying the presence of a biomarker in a reaction mixture, wherein said reaction mixture is produced by subjecting a biological sample from said subject to immunoprecipitation using an antibody followed by protease digestion,
• wherein said antibody binds to an amino acid sequence defined by amino acids 282-297 of U-p53, and said identification comprises mass spectrometry,
• wherein presence of said biomarker is indicative of Alzheimer's disease in said subject,
• wherein said biomarker comprises two or more of post-translation modifications (PTMs) in the region of amino acids 1-371 of the p53 protein (U-p53) selected from the group consisting of PTM-1, PTM-3, PTM-4, PTM-5, and PTM-6,
• wherein said PTM-1 is at the amino acid M1 of said U-p53, said PTM-3 is at the amino acid K370 of said U-p53, said PTM-4 is at the amino acid L101 of said U-p53, said PTM-5 is at the amino acid K120 of said U-p53, and said PTM-6 is at the amino acid K132 of said U-p53.

A method for diagnosing a subject as cognitively unimpaired or as having a neurodegenerative disease, the method comprising the step of:

• a) analysing a sample for the presence of post-translation modifications (PTMs) in the region of amino acids 1-371 of the p53 protein (U-p53), said PTMs being:
• PTM-1 at the amino acid M1,
• PTM-2 at the amino acid K164,
• PTM-3 at the amino acid K370,
• PTM-4 at the amino acid L101,
• PTM-5 at the amino acid K120,
• PTM-6 at the amino acid K132,
• PTM-7 at the amino acid K139,
• PTM-8 at the amino acid K291,
• PTM-9 at the amino acid K357,
• PTM-10 at the amino acid S6,
• PTM-11 at the amino acid S33,
• b) assessing the presence of:
• at least two PTMs selected from PTM-2, PTM-7, PTM-8, and PTM-11 is indicative of a cognitively unimpaired subject (CU),
• at least two PTMs selected from PTM-1, PTM-3, PTM-4, PTM-5, PTM-6, PTM-9, and PTM-10, and—at least one PTM selected from PTM-2, PTM-7, PTM-8, and PTM-11, as indicative of neurodegenerative disease, said neurodegenerative disease being selected from Mild Cognitive Impairment (MCI), Alzheimer's disease (AD), Fronto-temporal dementia (FTD), Lewi's Body (LB), and vascular dementia (VD),
• c) correlating the PTMs assessed in step b) with those identifying the corresponding neurodegenerative disease,
• wherein
• the presence of PTM-1, and PTM-10 is indicative of MCI;
• the presence of at least two PTMs selected from PTM-4, PTM-5, and PTM-9 is indicative of a prognosis of cognitive decline to AD of an asymptomatic subject;
• the presence of at least two PTMs selected from PTM-1, PTM-3, PTM-5, PTM-6, and PTM-10 is indicative of MCI with a prognosis of cognitive decline to AD;
• the presence of PTM-5, and PTM-9 is indicative of FTD;
• the presence of PTM-5, and PTM-6 is indicative of LB;
• the presence of PTM-4, and PTM-5 is indicative of VD.