Evaluation of a plasma protein panel as a compound biomarker for Alzheimers disease

Alzheimer?s disease is one of the most common and devastating of diseases of the elderly. As the population ages then the costs, already larger than cancer and heart disease combined, are set to rise substantially. Progress is being made in understanding the disease pathogenesis with the first disease modifying trials being reported this year. However, despite this progress, Alzheimer?s remains difficult to diagnose in the early stages, impossible to predict and even monitoring disease progression is difficult and subject to day to day variation and other sources of error. One way of overcoming these problems is the use of tests or biomarkers. Many such tests in development are dependent on access to sophisticated brain scanning or spinal fluid. We have taken an alternative approach in seeking blood based biomarkers. Studies in our laboratories over the past five years have revealed a set of markers that differ between Alzheimer?s patients and other elderly people. We propose now to develop these further into a test and then to trial this test on a large number of people. We will determine in this way, whether these proteins, together or separately, do function as a test in Alzheimer?s disease either for early diagnosis, for prediction of dementia or for monitoring disease progression. If they do, and the evidence so far is promising, then this has the potential to substantially improve diagnosis and to make trials of drugs for Alzheimer?s faster and more accurate to perform.

Using gel based proteomics we have identified a panel of potential plasma biomarkers for Alzheimer?s disease. These proteins have been replicated in moderately large subject populations of 200-500 subjects and subsequently the same proteins or closely related proteins have been identified in similar, independent studies, including those of our collaborators. These proteins together show promise as a compound marker for Alzheimer?s disease ? for example a sub-set of just five of the proteins predict brain volume, a marker of disease, in 80% of subjects. Having replicated, or partially validated, this set of proteins we now need to develop a stable and fully quantitative and sensitive assay and to test this on very large numbers of subjects, including population based cohorts. We plan to develop dual immunocapture and mass spectrometry based multiplexed assays and in a staged design determine the characteristics of the resulting compound assay as a marker of diagnosis, prediction and progression. We have, through this collaborative group, assembled a very large set of well characterised subjects for such studies including the main US and European AD Biomarker collections and population based sample sets including the MRC CFAS study. The study led by the MRC Centre for Neurodegeneration brings together expertise in Alzheimer?s disease, in assay design and development, in population based analyses and in statistics. The set of markers we have developed to date are, to our knowledge, the best characterised set developed through proteomics and are ready for further development and translation to clinical utility.