Molecular Insights into the Pathogenesis of Alzheimer’s Disease and Its Relationship to Normal Aging

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains.

Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism.

Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism.

The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process.

In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer’s disease progression.

Citation

Citation: Podtelezhnikov AA, Tanis KQ, Nebozhyn M, Ray WJ, Stone DJ, et al. (2011) Molecular Insights into the Pathogenesis of Alzheimer’s Disease and Its Relationship to Normal Aging. PLoS ONE 6(12): e29610. doi:10.1371/journal.pone.0029610

Editor: Maria A. Deli, Biological Research Center of the Hungarian Academy of Sciences, Hungary

Received: May 27, 2011; Accepted: December 1, 2011; Published: December 28, 2011

Copyright: © 2011 Podtelezhnikov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The Harvard Brain Tissue Resource Center, which generously provided the tissue samples, is supported by federal grant # R24 MH/NS068855. The profiling and the analysis were funded by Merck & Co., Inc. The manuscript was reviewed and approved for publication by Merck. The funders had no other role in study design, data collection and analysis, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.