Study Finds Genes Linked to Hippocampal Atrophy.
In a genome-wide association study, researchers from the BU Schools of Medicine and Public Health (BUSPH) have identified several genes which influence degeneration of the hippocampus, the part of the brain most associated with Alzheimer disease.
The study, which appears online as a Rapid Communication in the Annals of Neurology, demonstrates the effectiveness of genetically determined phenotypes in broadening the understanding of the genetic basis of, and pathways leading to, Alzheimer’s disease (AD).
Alzheimer’s is a progressive neurodegenerative disorder for which there is no proven prevention. Available drugs only marginally affect the disease severity and progression, making AD effectively untreatable.
Genome-wide association studies (GWAS) using large samples have increased the number of robust associations to 10 genes, but those genes account for no more than 35 percent of the inherited risk of Alzheimer’s disease. Most of the genetic underpinning of the disorder remains unexplained.
According to the research team, magnetic resonance imaging (MRI) of the brain provides quantitative measures of neurodegenerative and cerebrovascular brain injury that may represent AD-related changes, long before clinical symptoms appear. The measures are more powerful than comparisons of individuals with AD to cognitively healthy people, because they avoid misclassification of people who may develop disease in the future, the researchers said.
The research team conducted a two-stage study for quantitative measures of hippocampal volume (HV), total cerebral volume (TCV) and white matter hyperintensities (WMH). Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African-American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer’s Genetic Epidemiology) Study. In addition, similar MRI measures were obtained from 168 AD cases, 336 individuals with mild cognitive impairment, and 188 controls (all Caucasian).
Novel genome-wide significant associations were observed for hippocampal volume.
“Our two-stage GWAS identified highly significant associations between a measure of degeneration in the brain region most strongly correlated with AD and several genes in both Caucasian and African American samples containing AD, cognitively impaired and cognitively healthy subjects,” the researchers said. One of these associations was with the so-called ε4 variant of APOE, which is the most well-established genetic risk factor for AD; others were associated with genetic markers not previously implicated in the disease.
Senior author Lindsay Farrer, chief of biomedical genetics at BUSM and professor of epidemiology and biostatistics at BUSPH, said he believes it is likely that the number and specificity of these associations will increase in future studies, using larger samples and focusing on additional structural and functional MRI measures.
“These findings will inform experiments designed to increase our understanding of disease-causing mechanisms and may lead to new therapeutics’ targets,” Farrer said.
Other BUSPH researchers on the study included Kathryn Lunetta, professor of biostatistics. Researchers from Massachusetts General Hospital, Indiana University School of Medicine, and University of California at Davis also collaborated on the study.
The study was supported by the National Institute on Aging (NIA), the Dana Foundation and the National Institutes of Health Clinical and Translational Science Institute.
Submitted by: Lisa Chedekel
chedekel@bu.edu