Genetics and early onset Alzheimer's disease
There are two types of Alzheimer's disease - early onset and late onset. Early onset Alzheimer's is also called familial Alzheimer's because it runs in families. It is genetic in origin. A significant proportion of early onset Alzheimer's is linked to three genes: presenilin 1, presenilin 2, and A-Beta or amyloid precursor protein. If you have one of these three genes, it would be very unusual not to develop Alzheimer's before the age of 65. Early onset Alzheimer's is defined as Alzheimer's that strikes people before the age of 60 to 65 and often before the age of 55. It has been known to develop between the ages of 30 and 40, but that is exceedingly rare. Early onset is most common in someone in their 50s. Early onset Alzheimer's is a rare form of dementia. Only 6 to 8 percent of all people who have Alzheimer's have this early onset form.
Late onset Alzheimer's and the ApoE-e4 gene
In contrast to early onset Alzheimer's disease, late onset Alzheimer's has no known cause and shows no obvious inheritance pattern. For this reason it is also called sporadic Alzheimer's disease. The only risk factor gene identified so far for late onset Alzheimer's disease is a gene that makes one form of a protein called apolipoprotein E (ApoE). Everyone has ApoE, which helps carry cholesterol in the blood. There are three forms of the ApoE gene. Different forms of the same gene are called alleles. The three alleles of the ApoE gene are known as e2, e3, and e4. Everyone receives one of these three alleles from each parent. Thus the possible combinations in one person are e2-e2, e2-e3, e2-e4, e3-e3, e3-e4, e4-e4. Having one or two copies of the e4 allele increases a person's risk of getting Alzheimer's, but it does not mean that Alzheimer's is certain. Some people with two copies of the e4 allele (the highest risk group) do not develop clinical signs of Alzheimer's disease, while others with no e4 do. The ApoE-e3 allele is the most common form found in the general population and may play a neutral role in Alzheimer's disease. ApoE-e2 is the least common form and appears to be associated with a lower risk of Alzheimer's.
About 15% of the general population had the ApoE-e4 allele, and about 40% of people with Alzheimer's disease do. Thus, the gene for the ApoE-e4 allele is found about three times as frequently in persons with sporadic Alzheimer's as in age-matched control subjects. But the exact degree of risk for any given person cannot be determined based on ApoE status. As I said previously, inheriting the ApoE-e4 allele doesn't mean that a person has a certainty of developing Alzheimer's. Some people with the gene never develop Alzheimer's, and, conversely, there are people with Alzheimer's who do not have the gene. Therefore, ApoE-e4 is called a risk factor gene for late onset Alzheimer's disease. It is not predictive.
Two studies on genetics vs. environment
Japanese-Americans in Hawaii
There is evidence that environmental influences, such as diet and lifestyle, account for at least as much susceptibility to sporadic Alzheimer's disease as do genetics. A study of Japanese-American men in Hawaii implies that diet and lifestyle play a significant role in the development of Alzheimer's. The overall prevalence of dementia in Japan is similar to that in the United States and Europe. However, the prevalence of the different types of dementia is reversed. In Japan, vascular dementia is more common than Alzheimer's dementia. In the United states and Europe, Alzheimer's disease is more prevalent than vascular dementia. To be specific, vascular dementia is up to 3 times more prevalent in Japan than Alzheimer's dementia. In European and American studies, Alzheimer's dementia is 2 times more prevalent than vascular dementia. (Vascular dementia is a disease of the arteries that supply blood to the brain. Alzheimer's is a disease of the nerve cells in the brain.)
In the Honolulu-Asia Aging Study published in the Journal of the American Medical Association in 1996, L. White and other researchers found the prevalence of Alzheimer's disease in older Japanese-American men in Hawaii to be higher than in Japan and similar to European and American Caucasians. The difference between the Japanese in Japan and the Japanese in Hawaii is not genetics but environment, that is, diet and lifestyle.
African Americans in Indianapolis and Africans in Nigeria
Even more cogent evidence supporting the possibility that environmental influences have more impact on the development of Alzheimer's disease than do genetics can be found in a study by H. C. Hendrie and others published in the Annals of Psychiatry in October 1995. The title of this article is, "Prevalence of Alzheimer's disease and dementia in two communities: Nigerian Africans and African Americans." This was a study on the prevalence of dementia and Alzheimer's disease among two groups of subjects with the same ethnic background but widely differing environments. The study was conducted among residents aged 65 and older in two communities: Yoruba living in Ibadan, Nigeria, and African Americans living in Indianapolis, Indiana.
The age-adjusted prevalence rate for Alzheimer's disease in the Ibadan sample was significantly lower than in the Indianapolis sample: Among the Yoruba in living in Ibadan, Nigeria, the prevalence rate for Alzheimer's disease was 1.41%; among the African Americans in Indianapolis, Indiana, the rate was 6.4%. The prevalence of Alzheimer's disease in African Americans was more than four times the prevalence rate of Alzheimer's disease in Nigerian Africans.
The authors note that this was the first study, using the same research method and the same group of investigators at two different sites, to report significant differences in rates of Alzheimer's disease in two different communities with similar ethnic origins.
If genetics were the primary risk factor in Alzheimer's disease, Japanese Americans and African Americans would have a risk of developing Alzheimer's very similar to that of individuals living in their ancestral homes.
Can Environment Modify Genetics?
Alzheimer's disease is most likely the result of multiple genetic and multiple environmental influences; however, the environmental factors can modify genetic factors and determine whether or not they manifest as disease. In the study of the two communities in Ibadan, Nigeria, and Indianapolis, Indiana, there was a lack of association between Alzheimer's disease and possession of the ApoE-e4 allele in the Nigerian sample; whereas, there was a significant association between Alzheimer's disease and possession of this gene in the African American sample. The ApoE-e4 allele was strongly associated with Alzheimer's disease in the African American sample. The authors concluded that the differences between Nigerian subjects and African Americans would suggest involvement of environmental factors in the disease process.
Genetics Vs. Environment: Evidence From Identical Twins
Further evidence for the influence of environment in the development of Alzheimer's comes from studies of identical twins. Dr. Bill Beckwith, a noted memory expert in Fort Myers, told me the story of one of his patients, a terrified woman in her 60s. She had come to him for assessment of her mental capacity because her identical twin was in a nursing home with Alzheimer's disease. He found that she had an excellent memory and excellent mental skills.
The study of identical twins would be the perfect population to discover the degree to which Alzheimer's disease is determined by genetics because genetics is completely controlled for in this population. Fortunately, studies with twins have been done. The Swedish Twins Registry was established in the early 1960s and includes data on more than 15,000 fraternal and identical twins. A study using data from this registry was published by Margaret Gatz and other researchers in the April 2005 issue of Neurobiological Aging. This study is entitled, "Complete ascertainment of dementia in the Swedish Twin Registry: The HARMONY Study." This study found that the "concordance rate" for Alzheimer's disease among identical twins - meaning both twins either have dementia or both do not - ran about 60%. The concordance rate was 32% for fraternal twins of the same sex and 24% for fraternal twins of the opposite sex. The authors concluded that the results of the study mean that about 60% of Alzheimer's can be attributed to genes, but 40% can be traced to environment.
However, it could be argued that even more than 40% of Alzheimer's disease can be attributed to environment because twins usually share the same environment, at least during the formative years of their lives. Therefore, part of the concordance rate for Alzheimer's among identical twins could be the result of their shared environment as well as their shared genetics.
Since sporadic Alzheimer's disease is not completely genetic, but influenced by environmental factors, its onset can be modified by finding out what the environmental risk factors for Alzheimer's disease are and avoiding them where possible. The first of these risk factors will be the topic of next week's article.
Mary Lou Williams, M. Ed., is a lecturer and writer in the field of nutrition. She welcomes inquiries. She can be reached at 267-6480.