Q23. Is dementia an accelerated process of aging?
A23. In my opinion there are many reasons to distinguish between usual aging and Alzheimer disease, but from a scientific perspective, the distinction has not yet been completely proven.
We know that there are many people who live into their 90s and even past age 100 who do not have symptoms of dementia. We also know that as a group, the brains of people with dementia are different from the brains of people who do not have dementia at every age. Furthermore, the mild declines in word retrieval and speed of performance that accompany healthy aging are different from the impaired ability to learn new information and organize daily life that are characteristic of most people with mild cognitive impairment (MCI) and early Alzheimer disease.
Everyone over the age of 85 has tau deposits in their brain, and many people who have tested as cognitively normal within a year or two of death have other pathological abnormalities, such as neuritic plaques, small strokes, Lewy bodies, and scarring in the hippocampus. Some people cite these findings as evidence in favor of the idea that dementia develops from an “aging” process.
In the past several years, scientists have learned that aging is associated with an increasing likelihood of developing gene mutations that can cause cancer. I do not think we would consider this “normal,” but it is certainly an aging-associated process. The same might be true for the protein abnormalities that underlie progressive neurodegenerative dementias such as Alzheimer disease, Lewy body dementia, Parkinson disease, Parkinson disease dementia, and the tauopathies. That is, as we age, the likelihood increases that abnormal forms of certain brain proteins develop. If these abnormal proteins then slowly spread throughout the brain, dementia results. This is only a hypothesis, but it would help explain the strong association between aging and the risk of developing dementia.
Q24. Is Alzheimer disease hereditary?
A24. The answer to this question turns out to be complex.
People who inherit an abnormality in 1 of 3 genes, called “PS1,” “PS2,” and “APP” (amyloid precursor protein), develop Alzheimer disease, almost always before the age of 65. These genes are very rare in the population and account for 1% to 2% of all cases of Alzheimer disease.
50% to 60% of the risk of developing the common late-onset form of Alzheimer disease is related to more than 25 genes. Here’s where the genetics gets very complex and is not fully understood.
One of these genes, called the “APOE gene,” contributes about half of this genetic risk. The other half is contributed by the remaining 25 or so genes.
The APOE gene has 3 forms, labeled 2, 3, and 4. Each is considered a “normal” gene variant. Since we inherit 1 copy of the APOE gene from each parent, we can have 1 of 6 possible combinations of the APOE gene. This means each of us is either 2/2, 2/3, 2/4, 3/3, 3/4, or 4/4.
The 4 form of the gene (labeled “APOE4” or “APOE ε4”) increases the risk of developing Alzheimer disease, such that people who are 2/4 or 3/4 have a 2.5 to 3 times greater risk of developing Alzheimer disease than people who do not have a 4 form of the APOE gene. A person who inherits 2 copies of the 4 gene (4/4) has about a 12 times greater risk of developing Alzheimer disease than someone who has no copies of the 4 form of the gene. There is good evidence that the 2 form of the gene actually lowers the risk of developing Alzheimer disease.
Surprisingly, the APOE4 gene is not 100% determinative. A number of people have been identified who are very old, have 2 copies of the APOE4 gene, and do not have Alzheimer disease.
If two-thirds or so of the risk of developing Alzheimer disease is genetic, then roughly one-third is nongenetic or environmental. It is a mistake, then, to think that what happens in life is either “genetic” or “environmental.” This used to be referred to as the “nature vs. nurture” or “gene vs. environment” debate. It turns out that most common diseases do not follow this either-or model—they are caused by interactions between genetic risk factors and environmental risk factors. This is a whole new understanding of illness. Much research is needed to explain how such interactions cause disease.
Q25. Should I get genetic testing if my mother has Alzheimer disease?
A25. If a parent, brother, or sister (all referred to as “first-degree relatives”) has clinically diagnosed Alzheimer disease, then your risk of developing Alzheimer disease is 2.5 times to 3 times more likely than someone whose parents and siblings (brothers and sisters) did not develop Alzheimer disease.
It is easy to obtain genetic testing through over-the-counter gene testing kits such as 23andMe. However, before you do so you should understand what these tests can and cannot tell you. The best source of information about genetic testing is a trained genetic counselor, but most people either do not have access to such an expert or do not think they need to seek out their advice. In the next few paragraphs I will try to simplify what is a very complex issue.
As discussed in Q24, the APOE gene is the strongest genetic factor affecting the risk of developing the common form of Alzheimer. Over-the-counter gene-testing kits test for this gene.
In thinking about the value of these tests, it is important to know that the risk that any individual will develop Alzheimer disease by age 80 is, conservatively speaking, about 20%. This risk rises to about 35% if the person has 1 copy of the APOE4 gene. If a person has only APOE2 or APOE3 copies of the APOE gene, then that person’s risk of developing Alzheimer disease by age 80 decreases to about 15%. Thus, undergoing genetic testing for the APOE gene tells most people whether their risk of developing Alzheimer disease by age 80 is 15% or 35%. For the small number of people who have 2 copies of the APOE4 gene—about 5% of the population—the risk of developing dementia by age 80 is significantly higher.
To me, a 15% risk is significant and the difference between 15% and 35% is small. This has led me to conclude that every adult has a meaningful risk of developing Alzheimer disease by age 80, because the average life expectancy in the United States is 80 years for women and almost 79 years for men.
My own conclusion is that genetic testing for Alzheimer disease can tell people who have a family member with onset before age 60 whether they have inherited a copy of the PS1, PS2, or APP gene mutations and are at very high risk of developing Alzheimer disease (see Q24). For everyone else, the test kits give very little information beyond what we know already from population risk statistics: Everyone is at risk of developing Alzheimer disease if they live long enough, since many people with no APOE4 gene develop the disease. If knowing your genetic risk information would lead you to live your life differently, then you should probably consider doing so, no matter what the gene test shows.
I recognize that many people believe that genetic information would make a difference to them. I have no problem with making such tests and information available to them as long as they understand what the results can and cannot tell them. Not surprisingly, research shows that many people who get tested are hoping they will find out they are not at increased risk. My advice is that you should get tested only if you want to know if your risk is 15% or 35% at age 80, if you want to know whether you are one of the small percentage of people who have 2 copies of the APOE4 gene and are at much higher risk, or if you have family members with the disease who developed symptoms before age 60 or 65, in which case the possibility is increased that you have inherited one of the abnormal dominant PS1, PS2, or APP genes.
People who are concerned about a family history of frontotemporal dementia or Huntington disease should contact a genetic counselor if they are considering being tested.
Q26. Why do researchers think that the beta-amyloid protein or the tau protein causes Alzheimer disease? How do medications for treating Alzheimer disease target these proteins?
A26. As described in Q7, Alzheimer disease is characterized by 2 microscopic brain abnormalities: neuritic plaques, which consist of the protein beta-amyloid surrounded by pieces of dead nerve cells, and neurofibrillary tangles, which consist of twisted fibers made up of the protein tau.
There are many lines of evidence supporting the hypotheses that these abnormal proteins, either singly or in combination, are the cause of, or directly contribute to, the death of brain cells in Alzheimer disease. However, since this connection has not been proven, it is still possible that plaques and tangles are only markers for some other disease process that has yet to be discovered.
Evidence has been mounting that the beta-amyloid protein starts accumulating in the brain 15 to 20 years before the first symptoms of Alzheimer disease. Most studies find that tau is deposited in the brain closer to when symptoms start.
The amyloid protein seen in the neuritic plaque (see the figure in Q7) is derived from a larger protein called the “amyloid precursor protein (APP).” APP is a normal constituent of the cell membrane of every neuron. When brain neurons die, the APP is broken down into fragments by enzymes. These fragments are then removed from the brain through the spinal fluid that bathes the brain, through the bloodstream, and through another system, called the “lymphatic system” (see Q29).
However, some people are prone to form a fragment of the amyloid precursor protein called “A beta42” (because it is 42 amino acids long). A beta42 is too large to be removed from the brain, and therefore accumulates. The amyloid theory of Alzheimer disease is based on the finding that this A beta42 is toxic and kills other brain neurons. The dead cells then release more A beta42, which kills more brain cells. This ever-increasing cascade of cell death is the cause of dementia, according to this theory.
This hypothesis might be thought of as a problem in “garbage disposal.” If the A beta42 could be removed, the theory goes, then the whole cycle of cell death causing more A beta42 causing more cell death could be halted.
Many of the drugs in development to treat Alzheimer disease have targeted this “amyloid cascade.” Drugs have been designed to remove the toxic A beta42 protein, to decrease the production of the A beta42 protein, or to increase the production of the “nontoxic” form of A beta (A beta40). So far, none of these drugs has slowed or stopped the progress of Alzheimer disease in humans, although some have been successful in removing A beta42 protein from the brains of people with Alzheimer disease.
People with Down syndrome all develop the plaques and tangles characteristic of Alzheimer disease by the time they reach their 40s and are at higher risk for developing the dementia of Alzheimer disease by their 60s. The increased risk is likely related to the cause of Down syndrome, which is an extra copy of chromosome 21, on which is located the gene that makes the amyloid precursor protein (see Q24). As a result of their extra chromosome 21, people with Down syndrome have 3 copies of the APP gene rather than 2, and they produce 50% more of the amyloid protein.
The second abnormality in Alzheimer disease, the neurofibrillary tangle (see the figure in Q7), is made up of abnormal forms of the tau protein. Normally this protein is part of skeleton-like structures within cells which help the cell keep its shape. In Alzheimer disease, these structures become abnormal and lead to cell death. The amount of tau in the brain correlates with the severity of Alzheimer disease, so tau, too, has been a target of drug development. One drug designed to remove tau from the brain has failed to slow the disease. Other drugs are being developed to remove or prevent the deposition of the tau protein.
Several explanations have been proposed for the failure of the anti-amyloid and anti-tau approaches. One is that the drugs have been started too late in the disease process—remember, the A beta42 protein is being deposited 15 to 20 years before the first symptoms. A second potential reason is that both the A beta42 protein and the tau protein need to be removed. A third possibility is that some other process initiates the formation of plaques and/or tangles, and this other process must be identified and targeted if a treatment is to work. A final possibility is that alternative approaches are needed to better remove these abnormal proteins.
Q27. Are there environmental causes of Alzheimer disease?
A27. Yes. Nongenetic and environmental factors appear to contribute 30% to 50% of the risk of developing Alzheimer disease. Potentially changeable risk factors that have been identified are high blood pressure in midlife and less early-life education. Some studies have found increased rates of Alzheimer disease in people who have experienced depression in the past, engaged in less physical activity, were less engaged socially, are overweight, have hearing impairment, have elevated blood lipids, and have had a prior head injury.
As discussed in Q80 and Q81, environmental risk factors and genetic risk factors interact. Many genes establish a vulnerability, but disease emerges only if an environmental trigger is present. This radical rethinking of how diseases are caused is just beginning to affect how doctors treat and prevent disease.
Q28. What do you think about the theory that Alzheimer disease may be “germ” related?
A28. Several lines of scientific evidence support this possibility. One is that the amyloid precursor protein (APP) (see Q24 and Q26), a protein that is in the cell membrane of every neuron in the brain, functions as an anti-infection protein. If this is accurate, then some infectious agent might cause the release of APP and start the cascade that leads to the deposition of the amyloid (A beta42) that is characteristic of Alzheimer disease (see Q26).
Another possible link to infection is indirect evidence that a herpes virus infection earlier in life is linked, many years later, to the formation of the plaque lesions of Alzheimer disease.
A third possible link to an “infectious” process involves prions, a name derived by combining letters from the words proteinaceous, infectious, and particle (“ons” means “particle”). Prions cause Creutzfeldt-Jakob disease (CJD) and the related “mad cow disease” (officially called “variant Creutzfeldt-Jakob disease,” or “vCJD”), both of which cause a rapidly progressive dementia. The prion protein is a normal protein that can transform into an abnormal form that has the amazing ability to make copies of itself. These copies continue to multiply, enter nearby cells, and cause cell death. Because vCJD and some forms of CJD are acquired from eaten, injected, or implanted tissues that contain abnormal prions, they are considered infectious, and in that way act like “germs.”
Prions do not cause Alzheimer disease, Lewy body dementia, Parkinson disease dementia, or frontotemporal lobar dementia, but the mechanism by which prions spread through the body and brain might be similar to the mechanism by which the abnormal protein characteristic of each of these diseases spreads within the brain.
Q29. I know that disrupted sleep can be a symptom of Alzheimer disease, but I have heard that disturbed sleep might be a cause of Alzheimer disease. Is there any truth to that idea?
A29. Disrupted sleep has long been known to be associated with Alzheimer disease (see Q78). Recent studies suggest that the beta amyloid protein is removed from the brain by the lymphatic system, a system of connected tubules that drain fluid and immune cells. In mice, the lymphatic removal of amyloid protein breakdown products from the brain occurs at night—raising the possibility that in humans, disrupted sleep decreases the removal of these breakdown products and the tau protein, and thereby leads to Alzheimer disease. Conversely, Alzheimer disease might directly damage the areas of the brain that control sleep and thereby decrease the lymphatic system’s ability to remove amyloid.