HIPPOCAMPAL AND INTRACRANIAL VOLUME
Among the findings, both the CHARGE and ENIGMA groups identified a variant near a candidate gene called TESC (tescalin) associated with hippocampal volume loss — as much as 1.2 percent smaller — than control brains.
The ENIGMA group also identified and associated another variant in HMGA2 (high-mobility group AT-hook 2) with intracranial brain volume and intelligence. People with this variant have a brain that is on average half a percent bigger and they scored about 1.3 percent higher on IQ tests, the investigators reported.
Genes that regulate hippocampal volume may ultimately tip the cognitive scale in late life and increase a person's risk for Alzheimer disease, said Sudha Seshadri, MD, professor of neurology at the Boston University School of Medicine and one of the principal investigators of the CHARGE study. “Normally, people lose about five percent of volume every decade,” she said. Those in the early to moderate stages of Alzheimer disease have about a 10 percent difference in hippocampal volume than cognitively fit people of the same age, she added.
Somehow the variants impact hippocampal volume, which may diminish a person's so-called cognitive reserve, Dr. Seshadri continued. If Alzheimer's disease hits in late life this hippocampal vulnerability could hasten the disease process or lead to a more severe decline in cognitive function, she said.
Paul Thompson, PhD, professor of neurology at the David Geffen School of Medicine at the University of California, Los Angeles, and his colleagues at the Laboratory of Neuro Imaging, led the ENIGMA team. Dr. Thompson dubbed the international effort as “scientific social networking at its finest.” This type of analysis allows investigators to get a handle on what is going on in the brain over the lifespan, he said. “Some genes are vital for development but we might not be able to see their effects until late life.”
Dr. Seshadri said that with these genes and brain scans in hand, the scientists can follow the older adults in this study over time to see if a smaller intracranial or hippocampal volume leads to an increased risk for late life dementia.
“It's too early to say that we should screen people for genes associated with intracranial or hippocampal volumes but we can start studying these things to see if it does affect aging and if so, how. Gene environment and gene expression data will be important in mapping out the details,” she said.
D. Stephen Snyder, PhD, deputy director of the Division of Neuroscience at the National Institute on Aging, said that the genes “point to pathways but the extent to which any one pathway ultimately will matter in the development or progression of a neurodegenerative condition is open to debate.” As far as other neurological conditions, he added, “it is too early to say.”
Dr. Snyder was intrigued, he said, that even with population-based sampling of cognitively intact people that none of the gene variants most strongly associated with changes in hippocampal volume had ever shown up in genome-wide studies of Alzheimer disease.
“Perhaps the genetic risks of developing Alzheimer's and for hippocampal atrophy are ‘mechanistically distinct,’” he said, “that is, individuals who are cognitively intact and disease free can have a hippocampus that is ‘only’ diminished in volume while the hippocampus of individuals with Alzheimer's is so utterly vulnerable and wracked in persons with Alzheimer's.”
On the other hand, he said, it could be that these hippocampal volume risk genes (and single-nucleotide polymorphisms identified in this paper) are present in people with mild Alzheimer and that class of individuals would not have been examined in genome-wide studies conducted on the more advanced cases of Alzheimer or skewed by the apolipoprotein Egenotype.
• Bis JC, Decarli C, Seshadri S, et al, for the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium. Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nat Genet
• Taal HR, St. Purcain B, Wilson JF, et al. Common variants at 12q15 and 12q24 are associated with infant head circumference. Nat Genet
• Ikram MS, Fornage M, Wilson JF, et al, for the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants at 6q22 and 17q21 are associated with intracranial volume. Nat Genet
©2012 American Academy of Neurology
• Stein JL, Medland SE, Thompson PM, et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet
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