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Genetics, Transcriptomics, and Proteomics of Alzheimer's Disease

Andreas Papassotiropoulos, M.D.; Michael Fountoulakis, Ph.D.; Travis Dunckley, Ph.D.; Dietrich A. Stephan, Ph.D.; and Eric M. Reiman, M.D.

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.

(J Clin Psychiatry 2006;67:652-670)

Received Nov. 14, 2005; accepted Jan. 25, 2006. From the Division of Psychiatry Research, University of Zurich, Zurich, Switzerland (Dr. Papassotiropoulos); the Foundation for Biomedical Research of the Academy of Athens, Athens, Greece (Dr. Fountoulakis); and the Neurogenomics Division, The Translational Genomics Research Institute, Phoenix (Drs. Papassotiropoulos, Dunckley, Stephan, and Reiman); The Banner Alzheimer's Disease Institute, Phoenix, and the Department of Psychiatry, University of Arizona, Tucson (Dr. Reiman); and the Arizona Alzheimer's Disease Consortium, Phoenix (Drs. Dunckley, Stephan, and Reiman), Ariz.

Supported by grants from the Swiss National Science Foundation, Bern, Switzerland (PP00B 68859 to Dr. Papassotiropoulos), the National Institute of Mental Health, Bethesda, Md. (R01MH057899 to Dr. Reiman), the National Institute on Aging, Bethesda, Md. (P30AG19610
to Dr. Reiman.), and the State of Arizona (Drs. Stephan and Reiman).

The authors report no other significant commercial relationships relevant to the study.

Corresponding author and reprints: Andreas Papassotiropoulos, M.D., Division of Psychiatry Research, University of Zürich Lenggstrasse 31, P. O. Box 1931 CH-8032 Zürich, Switzerland