|Scientists Find New Genetic Clue to Cause of
Variations in a gene known as SORL1 may be a factor in the development
of late onset Alzheimer’s disease, an international team of researchers
has discovered. The genetic clue, which could lead to a better
understanding of one cause of Alzheimer’s, is reported in Nature
Genetics online, Jan. 14, 2007, and was supported in part
by the National Institutes of Health (NIH).
The researchers suggest that faulty versions of the SORL1 gene
contribute to formation of amyloid plaques, a hallmark sign of
Alzheimer’s in the brains of people with the disease. They identified
29 variants that mark relatively short segments of DNA where disease-causing
changes could lie. The study did not, however, identify specific
genetic changes that result in Alzheimer’s.
Richard Mayeux, M.D., of Columbia University, Lindsay Farrer,
Ph.D., of Boston University, and Peter St. George-Hyslop, M.D.,
of the University of Toronto, led the study, which involved 14
collaborating institutions in North America, Europe and Asia, and
6,000 individuals who donated blood for genetic typing. The work
was funded by NIH’s National Institute on Aging (NIA) and National
Human Genome Research Institute (NHGRI), as well as by 18 other
international public and private organizations.
“We do not fully understand what causes Alzheimer’s disease, but
we know that genetic factors can play a role,” says NIA director
Richard J. Hodes. M.D. “Scientists have previously identified three
genes, variants of which can cause early onset Alzheimer’s, and
one that increases risk for the late onset form. This discovery
provides a completely new genetic clue about the late onset forms
of this very complex disease. We are eager to investigate the role
of this gene further.”
Scientists think that in Alzheimer’s disease, amyloid precursor
protein, or APP, is processed into amyloid beta protein fragments
that make up plaques in the brain. The researchers began their
search for genetic influences amid a group of proteins that transport
APP within cells, looking for small changes, or “misspellings,” in
seven genes involved in moving APP within cells.
To start, the scientists combed two large data sets of genetic
information from families in which more than one person has Alzheimer’s
disease. They were soon able to see that many of the families with
Alzheimer’s had variations in the SORL1 gene but not consistently
in any of the other six genes.
They then expanded their search to genetic data sets from families
of Northern European, Caribbean Hispanic, Caucasian, African American,
and Israeli Arab heritage for changes in the SORL1 gene. Again,
they found same association between SORL1 variations and Alzheimer’s
disease. Searching additional data sets provided by Steven Younkin,
M.D., Ph.D., of the Mayo Clinic further confirmed the association
of SORL1 variations and Alzheimer’s.
“We are seeing the gene implicated in multiple data sets, across
ethnic and racial groups,” says Farrer. He adds that the group
was “encouraged and excited” by cell biology experiments that demonstrate
SORL1’s role in production of beta amyloid fragments.
Examining blood cells from people with and without Alzheimer’s,
the researchers found less than half the level of SORL1 protein
in people with Alzheimer’s compared to people without the disease.
In laboratory experiments, they found that altering the levels
of SORL1 changed the way APP was moved around in cells, with low
levels of SORL1 resulting in increased production of amyloid beta
fragments while high levels decreased production. However, the
researchers note, other genetic and non-genetic factors are likely
to affect SORL1 production in people, and more research is needed
to determine the how different versions of the SORL1 gene influence
production of the harmful protein fragments.
NIA and NHGRI support a number of studies looking at genetic factors
that may be involved in Alzheimer’s disease. For information on
the NIA Alzheimer’s Disease Genetics Study, which is currently
recruiting volunteers from families with two or more siblings affected
by late onset Alzheimer’s disease, visit the study web site, www.ncrad.org,
call 1-800-526-2839, or email firstname.lastname@example.org.
NIA leads the federal effort supporting and conducting research
on aging and the medical, social and behavioral issues of older
people, including Alzheimer’s disease and age-related cognitive
decline. For information on dementia and aging, please visit
the NIA's Alzheimer’s Disease Education and Referral Center at www.nia.nih.gov/alzheimers,
or call 1-800-438-4380. For more general information on research
and aging, go to www.nia.nih.gov.
NHGRI’s Division of Extramural Research supports grants for
a wide range of genetic and genomic research, as well as for
training and career development, at sites across the nation.
For more information about genomic research or NHGRI, go to www.genome.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.