Alzheimer's Disease : Beta-amyloid, Tau, Cardiovascular Risk

by National Institute on Aging

(Page 7 of 16)

A Different Genetic Story in Late-onset Alzheimer's Disease

While some scientists were focused on the role of chromosomes 21, 14, and 1 in early-onset Alzheimer's Disease, others were looking elsewhere to see if they could find genetic clues for the late-onset form. By 1992, these investigators had narrowed their search to a region of chromosome 19. At the same time, other colleagues were looking for proteins that bind to beta-amyloid. They were hoping to clarify some of the steps in the very early stages of the disease process. They found that one form of a protein called apolipoprotein E (ApoE) did bind quickly and tightly to beta-amyloid. They also found that the gene that produces ApoE was located in the same region of chromosome 19 pinpointed by the geneticists. This finding led them to suggest that one form of this gene was a risk factor for late-onset Alzheimer's disease.

Other studies since then have shown that the gene that produces ApoE comes in several forms, or alleles - e2, e3, and e4. The APOE e2 allele is relatively rare and may provide some protection against the disease. If Alzheimer's Disease does occur in a person with this allele, it develops later in life. APOE e3 is the most common allele. Researchers think it plays a neutral role in AD. APOE e4 occurs in about 40 percent of all Alzheimer's Disease patients who develop the disease in later life. It is not limited to people whose families have a history of AD, though. Alzheimer's Disease patients with no known family history of the disease are also more likely to have an APOE e4 allele than persons who do not have AD. Dozens of studies have confirmed that the APOE e4 allele increases the risk of developing Alzheimer's Disease. These studies have also helped to explain some of the variation in the age at which AD develops. However, inheriting an APOE e4 allele doesn't mean that a person will definitely develop Alzheimer's Disease. Some people with one or two APOE e4 alleles never get the disease and others who do develop AD do not have any APOE e4 alleles.

Although we still don't exactly know how APOE e4 increases Alzheimer's Disease risk, one theory is that when its protein product binds quickly and tightly to beta-amyloid, the normally soluble amyloid becomes insoluble. This may mean that it is more likely to be deposited in plaques.

While scientists are working to understand more fully the APOE gene and its role in AD, they have also identified regions on other chromosomes that might contain genetic risk factors. For example, in 2000, three teams of scientists, using three different strategies, published studies showing that chromosome 10 has a region that may contain several genes that might increase a person's risk of AD. Identifying these genes is one important step in the research process that will lead to new understanding about the ways in which changes in protein structures cause the disease process to begin and the sequence of events that occurs as the disease develops. Once they understand these processes, scientists can search for new ways to diagnose, treat, or even prevent Alzheimer's Disease.

Other Factors at Work in Alzheimer's Disease

Even if genetics explains some of what might cause AD, it doesn't explain everything. So, researchers have looked at other possibilities that may reveal how the Alzheimer's disease process starts and develops.

Beta-amyloid

We still don't know whether beta-amyloid plaques cause AD or whether they are a by-product of the disease process. We do know, however, that forming beta-amyloid from APP is a key process in Alzheimer's Disease. That's why finding out more about beta-amyloid is an important avenue of ongoing AD research. Investigators are studying: the nature of beta-amyloid, ways in which it is toxic to neurons, ways in which plaques form and are deposited, ways in which beta-amyloid and plaques might be reduced in the brain

Tau

In the last few years, scientists have been giving an increasing amount of attention to tau, the other hallmark of Alzheimer's disease. This protein is commonly found in nerve cells throughout the brain. In AD, tau undergoes changes that cause it to gather together abnormally in tangled filaments in neurons. In studying tau and what can go wrong, investigators have found that tau abnormalities are also central to other rare neurodegenerative diseases. These diseases, called tauopathies, include frontotemporal dementia, Pick's disease, supranuclear palsy, and corticobasal degeneration. They share a number of characteristics, but also each have distinct features that set them apart from each other and from Alzheimer's Disease. Characteristic signs and symptoms include changes in personality, social behavior, and language ability; difficulties in thinking and making decisions; poor coordination and balance; psychiatric symptoms; and dementia. Recent advances include the discovery of mutations in the tau gene that cause one tauopathy called frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The development of several mouse models that produce tau tangles, will allow researchers to address the many questions that remain about these diseases. The development of a "double transgenic" mouse that has both tau tangles and beta-amyloid plaques will also lead to further insights about AD.

Cardiovascular Risk Factors

Several recent studies in populations have found a possible link between factors related to cardiovascular disease and AD. One of these studies found that elevated levels of an amino acid called homocysteine, a risk factor for heart disease, are associated with an increased risk of developing Alzheimer's Disease. The relationship between AD and homocysteine is particularly interesting because blood levels of homocysteine can be reduced by increasing intake of folic acid and vitamins B6 and B12. In fact, in other studies, scientists have shown that folic acid may protect against nerve cell loss in brain regions affected by AD. Investigators have also found that the use of statins, the most common type of cholesterol-lowering drugs, is associated with a lower risk of developing Alzheimer's Disease.

About the Author

www.nia.nih.gov
NIA, one of the 27 Institutes and Centers of NIH, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life. In 1974, Congress granted authority to form NIA to provide leadership in aging research, training, health information dissemination, and other programs relevant to aging and older people.