An international team of researchers led by Boston University School of Medicine (BUSM) has identified four loci that appear to be associated with decreasing the volume of the hippocampus. The hippocampus is the region of the brain that plays an important role in the formation of specific, new memories, which is an ability that patients with Alzheimer's disease lose. The findings may have broad implications in determining how age, Alzheimer's disease and other diseases impact the function and integrity of the hippocampus.
Sudha Seshadri, MD, professor of neurology at BUSM, is a senior author of the study, which will be published online in Nature Genetics.
Previous research has shown that the hippocampus is one of the brain regions involved with short and long-term memory processes and that it shrinks with age. It also is one of the first regions to exhibit damage from Alzheimer's disease, which can cause memory problems and disorientation.
"One of the problems with studying the genetics of a disease like Alzheimer's, which becomes symptomatic later in life, is that many people die of other causes before they reach the age at which they might have manifested the clinical dementia associated with the disease," said Seshadri. "To get around this issue, we have been studying the genetics of traits that we know are associated with a high future risk of Alzheimer's disease but that can be measured in everyone, often 10 to 20 years before the age when most persons develop clinical symptoms."
The potential genetic traits are called endophenotypes, and hippocampal volume is one such trait. The hippocampus shrinks before and during the progression of Alzheimer's disease, but other factors, such as vascular risk factors and normal aging, also lead to the decrease in size.
"Our research team wanted to pinpoint the genetic causes of changes in the hippocampal volume in a sample of apparently normal older persons," said Seshadri.
The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium allowed the researchers to gather data on hippocampal volume from 9,232 people who did not have dementia. They identified four genetic loci, including seven genes in or near these loci that appear to determine hippocampal volume.
The results show that if one of the genes is altered, the hippocampus is, on average, the same size as that of a person four to five years older. These results were replicated in two large European samples that included a mixed-age sample that included some participants with cognitive impairment.
"The findings indicate that these loci may have broad implications for determining the integrity of the hippocampus across a range of ages and cognitive capacities," said Seshadri. One of the genes identified by the researchers was also shown to play a role in memory performance in a different data sample.
The identified genetic associations indicate that certain genes could influence cell death by apoptosis, brain development and neuronal movement during brain development, and oxidative stress. Additionally, the researchers found that the genes play a role in ubiquitination, which is a process by which damaged proteins are removed, whereas other genes code for enzymes targeted by new diabetes medications.
"Future studies need to further explore these genetic regions in order to better understand the role of these genes in determining hippocampal volume," added Seshadri.
One of the largest cohorts involved in the study was the Framingham Heart Study cohort, affiliated with BUSM. Seshadri is a Senior Investigator at the Framingham Heart Study.
"Such important research would not be possible without the ongoing dedication of the Framingham study participants, which now span three generations and six decades," said Seshadri.
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