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 Hispanics.
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).
National Institute on Mental Health