From proteomics to biomarker discovery in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. AD is an invariably fatal neurodegenerative disorder with no effective treatment or definitive antemortem diagnostic test. Little is known about the changes in the brain preceding or accompanying initiation of the disease. Understanding the biological processes, which occur during AD onset and/or progression, will improve the diagnosis and treatment of the disease. As we will discuss in this review article, using high-throughput cDNA microarray we identified candidate genes whose expression is altered in the brain of cases at risk for AD dementia. However, it is possible that the use of the cDNA microarray technology alone may underestimate post-transcriptional modifications and therefore provides only a partial view of the biological problem of interest. As such, the combination of cDNA and protein arrays may provide a more global picture of the biological processes being studied. Based on this hypothesis, we initiated a series of high-throughput proteomic studies and found that the expressions of proteins involved in synaptic plasticity are selectively altered in the brain of cases at high risk to develop AD dementia (mild cognitive impairment; MCI). This is consistent with our cDNA microarray evidence showing that the expression of a-type synapsins is selectively altered in the brain of MCI cases. Collectively, these studies support the feasibility and usefulness of high-throughput cDNA microarray and proteomics techniques to study the sequential changes of distinctive gene expression patterns in the brain as a function of the progression of AD dementia.