Diagnosing mild cognitive impairment (mci), predicting alzheimer's disease (ad) dementia onset, and screening and monitoring agents for treating mci or preventing dementia onset

Abstract

Methods of detecting the signature of Alzheimer's disease before the clinical onset of the disease are disclosed, such as methods of diagnosing Mild Cognitive Impairment (MCI), monitoring the progress of MCI, and predicting the time to clinical onset of AD dementia. The methods use a Biomarker Severity Score, which corresponds to output signals of one or more biomarkers chosen from AD Index, Morphometric Imaging, and PKC Epsilon Biomarkers. Also disclosed are methods of screening for a compound useful for treating MCI or for preventing the clinical onset of AD dementia, as well as methods of evaluating or monitoring the therapeutic benefit of an agent for treating MCI or preventing the clinical onset of AD dementia.

What is claimed is: 
     
         1 . A method of diagnosing Mild Cognitive Impairment (MCI) in a subject comprising:
 (a) obtaining one or more cells from the subject;   (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker; and   (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for age-matched control (AC) cells and for AD cells, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells.   
     
     
         2 . The method of  claim 1 , further comprising predicting the time to clinical onset of AD dementia, comprising:
 (1) plotting the output signals of the diagnostic biomarker for the AD cells as a function of their AD duration, wherein each AD duration is the age difference between the AD subject's age at the time of clinical onset of AD and the AD subject's age at the time of collecting one or more cells for generating the output signals of the diagnostic biomarker;   (2) fitting a function to the plotted output signals of step (1); and   (3) if MCI is indicated in step (c), predicting the time to clinical onset of AD dementia by inputting into the fit function the output signal of the diagnostic biomarker determined in step (b) and determining the time to clinical onset of AD dementia.   
     
     
         3 . The method of  claim 2 , wherein the fit function is a linear function. 
     
     
         4 . The method of  claim 1 , further comprising predicting the time to clinical onset of AD dementia, comprising:
 (1) plotting the output signals of the diagnostic biomarker for the AD cells as a function of their AD duration, wherein each AD duration is the age difference between an AD subject's age at the time of clinical onset of AD and the AD subject's age at the time of collecting one or more cells for generating the output signals of the diagnostic biomarker;   (2) plotting the output signals of the diagnostic biomarker for the AC cells as a function of their age difference, wherein each age difference is the difference between an AC subject's age at the time of collecting one or more cells for generating the output signals of the diagnostic biomarker and the age of the oldest AC subject at the time of collecting one or more cells for generating the output signals of the diagnostic biomarker;   (3) fitting a function to the plotted output signals of steps (1) and (2); and   (4) if MCI is indicated in step (c), predicting the time to clinical onset of AD dementia by inputting into the fit function the output signal of the diagnostic biomarker determined in step (b) and determining the time to clinical onset of AD dementia.   
     
     
         5 . The method of  claim 4 , wherein the fit function is a logistic function. 
     
     
         6 . The method of  claim 1 , further comprising monitoring the progression of MCI, comprising repeating steps (a) through (c) at one or more subsequent points in time, wherein the subject has progressed toward the clinical onset of AD dementia if the output signals determined in step (b) above have increased over time. 
     
     
         7 . The method of  claim 1 , wherein the output signals of the diagnostic biomarker for AC cells and AD cells in step (c) are average output signals. 
     
     
         8 . The method of  claim 1 , wherein the one or more cells are peripheral cells. 
     
     
         9 . The method of  claim 8 , wherein the peripheral cells are skin fibroblast cells. 
     
     
         10 . The method of  claim 1 , wherein the subject displays no phenotypic symptoms of AD. 
     
     
         11 . A method of screening for a compound useful for treating MCI or preventing the clinical onset of AD dementia comprising:
 (a) obtaining one or more cells from a subject;   (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker;   (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for AC cells and for AD cells, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells;   (d) if MCI is indicated in step (c), determining the output signal of the diagnostic biomarker in step (b) after contacting cells from the subject with a compound for an initial time period and/or for an ongoing time period; and   (e) comparing the output signal determined in step (d) to the output signal determined in step (b), wherein the test compound is indicated as useful for the treatment of MCI or the prevention of the clinical onset of AD dementia if the output signal determined in step (d) is less than the output signal determined in step (b).   
     
     
         12 . A method of evaluating or monitoring the therapeutic benefit of an agent for treating MCI or preventing the clinical onset of AD dementia in a subject comprising:
 (a) obtaining one or more cells from a subject;   (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker;   (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for AC cells and for AD cells, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells;   (d) if MCI is indicated in step (c), determining the output signal of the diagnostic biomarker in step (b) using one or more cells from the subject after initial, ongoing, and/or cessation of treatment with an agent; and   (e) comparing the output signal determined in step (d) to the output signal determined in step (b), wherein the agent is indicated as providing therapeutic benefit for treating MCI or preventing the clinical onset of AD dementia in the subject if the output signal determined in step (d) is equal to or less than the output signal determined in step (b).