An unprecedented international collaboration among virtually all the
scientists in the field of Alzheimer's disease (AD) genetics has provided
the clearest picture to date of how the APOE gene influences the disease in
relation to age, sex, race and ethnicity.
The study, published in the Journal of the American Medical Association,
examined raw data from about 15,000 AD cases and controls that were
contributed by 40 research teams and confirms a 15-fold increased risk for
Caucasians who inherit one specific APOE genotype known as 4/4. The large,
pooled data set, collected by a research team led by Lindsay Farrer, Ph.D.,
of Boston University School of Medicine, represents one of the largest
epidemiological studies of any specific gene.
"The findings on age, sex, race and ethnicity could not have been achieved
without the statistical power made possible by this unique collaboration, "
said Farrer. He indicated that this united effort to pool data from various
studies could serve as a paradigm for studying other complex genetic
diseases such as manic depressive illness, vascular dementia, autism,
cardiovascular disease, and diabetes.
ApoE, short for apolipoprotein E, a protein encoded by the APOE gene on
chromosome 19 and produced in the liver and brain astrocytes, comes in three
main forms, or alleles, known as 2, 3, and 4. There are six combinations,
or genotypes, possible in the world's population, since everyone has two
copies of the gene, receiving one from each parent.
The 3/3 genotype is the most common variant, occurring in about 65 percent
of the Caucasian population, and is not associated with an increased risk
for AD. Compared to people with this genotype, Caucasians who inherit the
4/4 variant are 15 times more likely to develop the disease. Although an
elevated frequency of the 4 allele was detected in AD cases in every ethnic
group studied, the association was weaker in African Americans and
Hispanics, said Farrer. In Japanese people, however, the association was
about twice as strong.
People who inherit the 2/3 genotype, the research also confirmed, seem to be
protected from developing AD by the 2 allele. Caucasians with the 2/3
variant develop the disease about half as often as those with the 3/3
variant. A similar protective effect was seen in African Americans and
A unique finding of the study, Farrer said, is that people with the 2/4
variant are more likely to develop AD than people with the 3/3 genotype,
despite the presence of the protective 2 allele.
With regard to age, this study found that the APOE-4 allele is a major risk
factor for AD for everyone between the ages of 40 and 90, although the risk
diminishes after age 60. The study is also the first to demonstrate that
the 4 allele confers risk to people as young as 40.
Gender differences play a role in susceptibility to AD, according to the
study results. Caucasian women with the 3/4 genotype are 1.5 times more
likely than men with the same genotype to develop the disease. Overall,
Farrer said, the study points to a higher susceptibility to AD for women
than men, regardless of their age or APOE genotype. Other factors such as
estrogen may account for the sex differences, he said.
Also participating in the study were: Richard Myers, Ph.D., Adrienne
Couples, Ph.D., Boston University; Jonathan Haines, Ph.D., Bradley Hyman,
M.D., Ph.D., Massachusetts General Hospital; Walter Kukull, Ph.D., University of
Washington; Richard Mayeux, M.D., Columbia University; Margaret
Pericak-Vance, Ph.D., Duke University; Neil Risch, Ph.D., Stanford
University; Cornelia van Duijn, Ph.D., Erasmus University.
This study, supported by a grant from the National Institute on Aging (NIA),
included data contributions from top scientists around the world, many of
them supported by NIA's Multi-Institute Research on Alzheimer's Disease
Genetic Epidemiology Study, the National Institute of Mental Health (NIMH),
and the National Institute of Neurological Disorders and Stroke (NINDS).
NIA, NIMH and NINDS are part of the National Institutes of Health, an agency
of the U.S. Department of Health and Human Services.