Genetics, transcriptomics, and proteomics of Alzheimer's disease

Abstract

Objective: To provide an updated overview of the methods used in genetic, transcriptomic, and proteomic studies in Alzheimer's disease and to demonstrate the importance of those methods for the improvement of the current diagnostic and therapeutic possibilities.

Data sources: MEDLINE-based search of 233 peer-reviewed articles published between 1975 and 2006.

Data synthesis: Alzheimer's disease is a genetically heterogeneous disorder. Rare mutations in the amyloid precursor protein, presenilin 1, and presenilin 2 genes have shown the importance of the amyloid metabolism for its development. In addition, converging evidence from population-based genetic studies, gene expression studies, and protein profile studies in the brain and in the cerebrospinal fluid suggest the existence of several pathogenetic pathways such as amyloid precursor protein processing, beta-amyloid degradation, tau phosphorylation, proteolysis, protein misfolding, neuroinflammation, oxidative stress, and lipid metabolism.

Conclusions: The development of high-throughput genotyping methods and of elaborated statistical analyses will contribute to the identification of genetic risk profiles related to the development and course of this devastating disease. The integration of knowledge derived from genetic, transcriptomic, and proteomic studies will greatly advance our understanding of the causes of Alzheimer's disease, improve our capability of establishing an early diagnosis, help define disease subgroups, and ultimately help to pave the road toward improved and tailored treatments.

Figure 1

Workflow for the proteomic analysis of the brain.

Figure 2

Proteins of total brain extract separated on a 2-D gel.

Figure 3

Example of a protein, in this case the synaptosomal protein 25 kDa (snap25), which shows reduced levels in the AD brain in comparison with the control brain. A: controls brain, B: AD brain.