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Alzheimer's, Dementia & Mental Health
New Gene Variant Found in Senior Citizens with
Alzheimer's Disease
SORL1 joins ApoE4 as genetic variant for
late-onset Alzheimer's
January 15, 2007 – A massive international study
 lasting five years indicates that a newly discovered gene –
SORL1 – is implicated in late-onset Alzheimer's disease. This is the
most common form of the disease, accounting for 90 percent of all cases
of Alzheimer's. It tends to affect senior citizens - those aged 65 and
older. With aging baby boomers now turning 60, the prevalence of
late-onset Alzheimer's is expected to double in the next 25 years.
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Alzheimer's, Dementia & Mental Health |
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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.
Replicated in four distinct ethnic groups, SORL1 is
only the second genetic variant for late-onset Alzheimer's. ApoE4, the
first, was identified in 1993.
The discovery was by researchers, led by Columbia
University Medical Center, Boston University School of Medicine and the
University of Toronto and involved 14 collaborating institutions in
North America, Europe and Asia, including the Mayo Clinic
They tested over 6,000 DNA samples from four
distinct ethnic groups: Caribbean-Hispanics, North Europeans,
African-Americans and Israeli-Arabs and uncovered two consistent
patterns that linked the SORL1 gene to people afflicted with
Alzheimer's.
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 Half of all
people who reach age 85 will likely be affected by Alzheimer’s
disease, with the onset age usually around 75. |
SORL1 governs the distribution of amyloid precursor
protein (APP) inside nerve cells of the brain. When working properly,
the SORL1 protein regulates APP by diverting it into specific certain
regions of the cell. When the level of the SORL1 gene is reduced, APP
accumulates in a different region of the cell, where it is degraded into
amyloid beta fragments – abnormal protein fragments – which then cause
Alzheimer's disease.
The authors believe that genetic variants alter the
normal function of SORL1, sending APP down a pathway that increases the
production of the toxic amyloid beta peptides in the brain resulting in
Alzheimer's. When the SORL1 gene works properly, it sends APP along
recycling pathways -- preventing it from being cut into the toxic
amyloid beta forms.
People with these genetic variants may not produce
normal amounts of SORL1, suggesting that this gene has protective
function when working properly. The researchers believe that the
reduction of SORL1 in the brain increases the likelihood of developing
Alzheimer's disease.
The research team at Columbia University Medical
Center was led by Richard Mayeux, M.D., co-director of the Taub
Institute for Research on Alzheimer's Disease and the Aging Brain. The
team at the University of Toronto was led by Peter St. George-Hyslop,
M.D., director of the Centre for Research in Neurodegenerative Diseases,
and the Boston University team by Lindsay Farrer, Ph.D., chief of the
Genetics Program. Steven Younkin, M.D., Ph.D., chair of Department of
Pharmacology at the Mayo Clinic College of Medicine in Jacksonville,
Fla. also provided DNA samples from the Mayo's respective unique
populations for the study.
"The importance of the finding is that it opens new
pathways to explore the cause and as well as potential targets for
treatment of this devastating disease," said Dr. Mayeux.
"SORL1 represents another critical piece of the
Alzheimer's disease puzzle. This appears to be the fifth Alzheimer's
disease gene, and there are likely to be other important genetic
variants that need to be identified before the entire picture is
complete."
"Instead of scanning all the genes in the entire
genome, we had an idea of what an Alzheimer's disease-causing gene would
look like based on past discoveries," said Dr. St. George-Hyslop. "We
knew that the abnormalities in APP processing and the accumulation of
its toxic amyloid beta peptide derivative cause Alzheimer's, so we
hypothesized that other genes associated with APP regulation might also
cause the disease."
"We discovered two different variants in the SORL1
gene that are associated with increased risk of AD in different ethnic
groups, says Dr. Ekaterina Rogaeva, first author of the study. "This
emphasizes the complexity of the genetics of common late-onset form of
Alzheimer's disease, and has important implications for replication
studies that would need to assess SORL1 variations in datasets with
similar genetic background."
Beginning of Study: Genetic Homogeneity of
Dominican Population Tapped for Discovery
In 1994, Mayeux noticed, upon studying elderly
residents of Washington Heights, a predominantly Hispanic neighborhood
in Northern Manhattan where Columbia University Medical Center is
located, that Dominicans have about three times the rate of Alzheimer's
disease compared to individuals of different ethnic backgrounds in the
community.
Mayeux decided to find out why this population has
such a high incidence of Alzheimer's, so he and his Columbia team began
visiting Dominican families living in both Washington Heights and the
Dominican Republic to collect blood samples of entire families in order
to look for similar gene variations in relatives diagnosed with
Alzheimer's.
"The Dominican population is very concerned about
the increased frequency of disease and was very helpful in forming the
basis of this study. From a genetic perspective, Dominicans are a
relatively homogenous population, and follow similar diet and living
patterns," said Mayeux.
"Because individuals within families stay in touch
and remain close to one another even after migrating to the United
States, we were able to identify families in this large population that
were very similar genetically."
To confirm their preliminary findings, Mayeux and
St. George-Hyslop, his collaborator of more than 25 years, reached out
to other colleagues who tapped genetic records of people of from even
more diverse ethnic backgrounds.
In total, the initial discovery group included 350
families (representing a total of 1,800 people, half of whom had
Alzheimer's), from Columbia University Medical Center and the University
of Toronto. The report on the research appears in an article published
in the Jan. 14 advance on-line edition of Nature Genetics (February
print edition).
The group was divided into two parts: one that was
analyzed to help with the discovery of SORL1, and a second that was
analyzed to confirm the role of the gene. To this collection, Dr. Farrer,
from Boston University School of Medicine, added 500 African-American
sibling pairs (representing a total of 1,000 people), where one sibling
was diagnosed with Alzheimer's and the other was not.
Farrer also enabled the researchers to reconfirm
their findings in an examination of data from Israeli-Arabs, while
Younkin's data from mostly white Alzheimer's patients provided by the
Mayo Clinic also confirmed the findings. Interestingly, the same variant
was found in both the Israeli-Arab and Caribbean-Hispanic groups, which
indicates that generations ago these two groups may have been
genetically or geographically linked.
Seeking Pathogenesis of SORL1 & Attributable Risk
of SORL1 Variants
"Now that we know that variants in SORL1 are
associated with late-onset Alzheimer's disease and we know the specific
regions of the gene involved, our next step is to determine which of the
variants contain the specific disease causing alteration," said Mayeux.
Another next step is to determine how many cases of
late-onset Alzheimer's are caused by these SORL1 variants; it is known
that ApoE4 explains approximately 20 percent of all cases of late-onset
Alzheimer's. Studies are planned to investigate how many Alzheimer's
cases are attributable to SORL1. The hope is that this information will
help develop accurate screening for this gene.
Because these genetic association studies are very
complex, the next step must be to get the result replicated by other
groups.
"Despite the breadth of the study, it's important
to have independent replication, which is the only way to be certain
that the results are generalizable," says Mayeux.
"SORL1 represents another critical piece of the
Alzheimer's disease-amyloid puzzle, but the work of identifying the
actual disease- causing mutations in SORL1, and understanding exactly
how they reduce SORL1 function remain ahead of us."
Boston University's Farrer also cautions that more
studies are needed. He says that while they have identified several
variants in SORL1 that show the same pattern of association across
multiple ethnic groups with very different genetic makeup and lifestyle
characteristics, it is unclear whether these variants influence the
disease process directly or merely mark the location in the SORL1 gene
of the biologically important variants which have not yet been tested.
"SORL1 is a big gene containing at least 500 known
variants called single nucleotide polymorphisms (SNPs)," Farrer says.
"We examined a representative sample of about 30 SNPs across SORL1 and,
unfortunately, have not yet found a 'smoking SNP' for Alzheimer's
disease."
"The recurring theme that genetic causes of
Alzheimer's all seem to impact the accumulation of amyloid beta-peptide
in the brain, and that potential therapies which block Aß production or
toxicity seem to block the disease in animal models, suggests that we're
on the right track," says Professor Steven Younkin, chair of Department
of Pharmacology at the Mayo Clinic College of Medicine.
"We do not fully understand what causes Alzheimer's
disease, but we know that genetic factors can play a role," says
National Institute on Aging 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."
Editor's Notes
Study Funding
This research was funded by the National
Institute on Aging of the National Institutes of Health, the Alzheimer's
Association of the United States, the Canadian Institutes of Health
Research, Howard Hughes Medical Institute, the Alzheimer Society of
Ontario, the Canada Foundation for Innovation, the Ontario Research and
Development Challenge Fund, Genome Canada and the Banbury Fund.
Facts about Alzheimer's Disease
Alzheimer's disease, which affects 4.5 million
Americans, is differentiated as either early-onset or late-onset. The
early-onset form is rare and tends to affect those between the ages of
30-60. Most cases of early-onset are genetic, caused by a mutation of
the APP gene. The late-onset form is much more common -- accounts for 90
percent of all cases of Alzheimer's -- and tends to affect those aged 65
and older. With aging baby boomers, the prevalence of late-onset
Alzheimer's is expected to double in the next 25 years as the population
ages.
National Institute on Aging
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,
http://www.ncrad.org/, call 1-800-526-2839, or email
alzstudy@iupui.edu.
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
http://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
http://www.genome.gov/.
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
http://www.nih.gov/.
Taub Institute
The Taub Institute for Research on Alzheimer's
Disease and the Aging Brain at Columbia University Medical Center is a
multidisciplinary group that has forged links between researchers and
clinicians to uncover the causes of Alzheimer's, Parkinson's and other
age-related brain diseases and discover ways to prevent and cure these
diseases. It has partnered with the Gertrude H. Sergievsky Center at
Columbia University Medical Center which was established by an endowment
in 1977 to focus on diseases of the nervous system. The Center
integrates traditional epidemiology with genetic analysis and clinical
investigation to explore all phases of diseases of the nervous system.
For more information about these centers visit:
http://www.cumc.columbia.edu/dept/taub/
http://www.cumc.columbia.edu/dept/sergievsky/.
Columbia University
Columbia University Medical Center provides
international leadership in pre-clinical and clinical research, in
medical and health sciences education, and in patient care. The medical
center trains future leaders and includes the dedicated work of many
physicians, scientists, nurses, dentists, and public health
professionals at the College of Physicians & Surgeons, the College of
Dental Medicine, the School of Nursing, the Mailman School of Public
Health, the biomedical departments of the Graduate School of Arts and
Sciences, and allied research centers and institutions. For more
information, visit
http://www.cumc.columbia.edu/.
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