Two research studies, co-led by UC Davis neurologist Charles DeCarli and
conducted by an international team that included more than 80 scientists at 71
institutions in eight countries, has advanced understanding of the genetic
components of Alzheimer's disease and of brain development. Both studies appear
in the April 15 edition of the journal Nature Genetics.
The first study, based on a genetic analysis of more than 9,000 people, has
found that certain versions of four genes may speed shrinkage of a brain region
involved in making new memories. The brain area, known as the hippocampus,
normally shrinks with age, but if the process speeds up, it could increase
vulnerability to Alzheimer's disease, the research suggests.
The second paper identifies two genes associated with intracranial volume --
the space within the skull occupied by the brain when the brain is fully
developed in a person's lifespan, usually around age 20.
DeCarli is a pioneer in the field of neuroimaging of the aging brain who has
been at the forefront of developing and using quantifiable imaging techniques to
define the relationship between structure and function in the healthy aging
brain and to characterize the changes associated with vascular and Alzheimer's
dementias. He is professor of neurology and director of the UC Davis Alzheimer's
Disease Center and the UC Davis Imaging of Dementia and Aging Laboratory.
Genetic variants of hippocampus study
The gene variants identified in the first study do not cause Alzheimer's, but
they may rob the hippocampus of a kind of "reserve" against the disease, which
is known to cause cell destruction and dramatic shrinkage of this key brain
site. The result is severe loss of memory and cognitive ability.
Scientists calculated that hippocampus shrinkage in people with these gene
variants accelerates by about four years on average. The risk of Alzheimer's
doubles every five years beginning at age 65, so a person of that age would face
almost twice the Alzheimer's risk if he or she had these versions of the
gene.
Looked at another way, if a person with one of these variants did get
Alzheimer's, the disease would attack an already compromised hippocampus and so
would lead to a more severe condition at a younger age than otherwise, the
research suggests.
"This is definitely a case of 'bigger is better,'" said DeCarli. "We already
know that Alzheimer's disease causes much of its damage by shrinking hippocampus
volume. If someone loses a greater-than-average amount of volume due to the gene
variants we've identified, the hippocampus is more vulnerable to
Alzheimer's."
Why the aging hippocampus normally decreases in volume is unclear. The new
research shows that the genes most strongly linked to shrinkage are involved in
maturation of the hippocampus and in apoptosis, or programmed cell death -- a
continual process by which older cells are removed from active duty.
The scientists suggest that if the gene variants they identified do affect
either maturation or the rate at which cells die, this could underlie at least
some of the increased rates of hippocampus shrinkage.
"Either by making more or healthier hippocampal neurons or preventing them
from dying with advancing age, the healthy versions of these genes influence how
people remember as they get older," said DeCarli. "The alternate versions of the
genes may not fully provide these benefits."
The researchers hope that they can find ways to protect the hippocampus from
premature shrinkage or slow its decline by studying the normal regulation of the
proteins coded by these genes.
The genetic analysis draws on what is known as a genome-wide association
study -- research aimed at finding the common genetic variants associated with
specific diseases or other conditions. Different versions of a gene usually come
down to changes in just one of the tens of thousands of DNA "letters" that make
up genes. These one-letter differences are known as single-nucleotide
polymorphisms, or SNPs.
The research involved more than 80 scientists at 71 institutions in 8
countries. Many researchers are needed for such a study in order to put together
the large samples, or cohorts, of people whose genetic makeup is to be
investigated, to measure the hippocampus from magnetic resonance pictures of the
brain and for the labor-intensive statistical analysis of the findings.
The study used a very large assemblage of genetic and disease data called the
Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium, or
CHARGE. The consortium brings together several population-based cohorts in the
United States and Europe.
The cohort was made up of 9,232 dementia-free volunteers with an average age
of 67. The study identified four different gene variants associated with
hippocampus volume decline. One, known as rs7294919, showed a particularly
strong link to a reduced hippocampus volume, suggesting that this gene is very
important to hippocampus development or health.
The findings were then assessed in two other cohorts. One, including both
normal and cognitively compromised people with an average age of 40, showed that
three of the suspect SNPs were linked to reduced hippocampus volume. Analysis of
results from the third group, comprised primarily of older people, showed a
significant association between one of the SNPs and accelerated memory loss.
"With this study, we have new evidence that aging, the hippocampus and memory
are influenced by specific genes," DeCarli said. "Understanding how these genes
affect the development and aging of the hippocampus may give us new tools to
delay memory loss with advanced age and possibly reduce the impact of such
diseases as Alzheimer's disease."
Genetic variants of Intracranial-volume study
While the first study deals with the genetic associations with brain
shrinkage, the second deals with associations impacting intracranial volume,
which is an indirect measure of the size of the brain at full development.
Though brain volume and intracranial volume are both highly heritable, the
genetic influences on these measures may differ. To assess the genetic influence
on these two measures, researchers in the second study performed a genome-wide
association study on cross-sectional measures of intracranial volume and brain
volume in 8,175 elderly in the CHARGE consortium.
They found no associations for brain volume, but they did discover that
intracranial volume was significantly associated with two loci: rs4273712, a
known height locus on chromosome 6q22, and rs9915547, tagging the inversion on
chromosome 17q21.
"Since geneticists are already familiar with the other functions of these
same genes, associating these particular genes with intracranial volume may help
us better understand brain development in general," said DeCarli. "For instance,
we know that one of these genes has played a unique evolutionary role in human
development, and perhaps we as a species are selecting this gene as a way of
providing further advances in brain development."
Both studies involved international teams representing scores of
institutions, funded by a variety of NIH grants as well as grants from agencies
around the world.
**Published in "SCIENCE DAILY"
