Genome-wide Study Links Metabolic Changes With Early Onset of Alzheimer’s

[Source: TGen] - Researchers at the Translational Genomics Research Institute (TGen) and their colleagues today report a finding that correlates significant under-expression of genes in certain brain regions with the pattern of metabolic deficits in the brains of individuals with Alzheimer’s. The findings provide new information surrounding the development of Alzheimer's disease and identify novel targets to consider when developing methods to diagnose and treat the disease. The results appear on-line in the Early Edition of the Proceedings of the National Academy of Sciences.

Alzheimer's disease is an irreversible, progressive disorder in which certain brain cells (called neurons) deteriorate, resulting in the loss of cognitive functions including memory, judgment and reasoning, movement coordination, and pattern recognition. In advanced stages of the disease, all memory and mental functioning may be lost. The progressive neurological disorder afflicts an estimated five million Americans, a number expected to triple by 2050.

“In the search for a cure for this common and devastating condition, the best hope lies in diagnosing who is at risk for the disease and treating it at its earliest stages,” said Dr. Dietrich Stephan, director of TGen’s Neurogenomics Division and the study’s senior author. “Through gene testing and functional brain imaging we can gauge an individual’s risk, and now we have a handhold into the biology underlying the earliest signs of the disease.”

Alzheimer’s is associated with reductions in regional positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose. These reductions have been reported in specific areas of brains afflicted by Alzheimer’s. In collaboration with the Arizona Alzheimer’s Consortium, Banner Alzheimer’s Institute, Barrow Neurological Institute, Sun Health Research Institute and others, TGen researchers compared 80 metabolically relevant genes specific to the cell nucleus from the brains of Alzheimer’s disease cases and controls. Samples were drawn from different regions of the brain affected to varying degrees by the disease. The researchers employed cutting-edge genomic technology to analyze cells in specific regions of the brain that are affected by Alzheimer’s. The results indicated that changes in expression of key genes correlate with metabolic changes known to contribute to the origins of Alzheimer’s disease.

“This is a very interesting finding because it pinpoints the molecular factors that may drive or influence metabolic deficits that characterize the brains of Alzheimer’s patients,” said Dr. Winnie Liang, a research associate in TGen’s Neurogenomics Division and the study’s first author.
When compared with controls, the Alzheimer’s cases had significantly lower expression of 70% of nuclear-encoding metabolism genes in the posterior cingulate cortex, the area of the brain that is metabolically affected in the earliest stages of Alzheimer’s disease. The researchers found a 65% reduction in expression in the middle temporal gyrus, and a 61% reduction in the hippocampal CA1, both regions of the brain that are involved in memory functions. Additionally, the researchers found only a 16% reduction in the visual cortex, a brain region that is relatively spared by Alzheimer’s disease.

While it is still unclear whether these expression changes cause metabolic reductions that are detected using PET or if these changes result from decreased metabolic demands, the results from this study lend insight into the processes that may drive Alzheimer’s pathogenesis early on and before the onset of measureable cognitive deficits.