Transcriptional Changes in Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia, affecting millions of aging people worldwide with no known cure. Pathological analyses have identified extracellular beta-amyloid plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau as core features, but the key causal biochemical pathways remain elusive. In fact, functional genomic analyses suggest a number of other cellular changes occurring early in the disease, including synaptic and bio-energetic dysfunction, as well as a role for neuron glia interactions. Given the complexity of AD and the limitations of our current knowledge, the field of AD research would benefit from taking hypothesis-independent approaches that allow one to view the data in a systems biology framework. This paradigm shift in AD transcriptional research would permit consolidation of the large body of often-conflicting transcriptional, proteomic, and other screening results into testable theories of AD progression. In this chapter, we will first review transcriptional studies of AD that use postmortem human brain, animal model systems, and peripheral human tissue, addressing the biological pathways that these studies suggest degrade with AD progression. Next, we will discuss recent studies with more multifaceted designs, and how results from such studies lend support to some of these theories. Finally, we will suggest how using a more systems-level approach to the study of AD could help scientists further clarify what goes wrong in the brain at various stages of AD progression and be beneficial for the development of more targeted therapies.