Risk factors for Alzheimer's disease

 | January 1, 2007

Risk factors for Alzheimer's disease

A number of factors have been linked to Alzheimer's disease. Age, heredity, sex, cardiovascular problems, and brain injury may play a part.

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Age and sex

Your age itself poses some risk, regardless of whether a family member has had Alzheimer's disease. The risk usually rises after age 65 and increases in subsequent years (see Table 2). Still, Alzheimer's is not an inevitable consequence of aging.

It also appears that women have a somewhat higher rate of Alzheimer's disease than men do. However, this effect might be due not to any biological factor, but to greater longevity.

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Genetic factors

When a family member has Alzheimer's, people often wonder about their own chances of developing the disease. While heredity is a major factor in a small number of families, for most people, genetics plays only a minor role or none at all.

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Early-onset Alzheimer's disease

Genetics is most important in families with a history of early-onset Alzheimer's (occurring before age 50) stretching back for several generations. (The early-onset form accounts for less than 1% of all Alzheimer's cases.) Mutations in three genes are known to cause this type of Alzheimer's: amyloid precursor protein gene (APP), presenilin 1, and presenilin 2. All three genetic mutations increase the production of beta-amyloid, which is deposited in the plaques found in Alzheimer's disease. APP directs the production of amyloid precursor protein, a brain protein that, when fragmented, sometimes produces beta-amyloid.

If one parent has any of these mutations, each child has a 50% chance of inheriting the mutated form. A child who inherits the mutated gene will inevitably develop early-onset Alzheimer's disease.

The defective APP gene, found in some families with early-onset Alzheimer's, is located on chromosome 21. People with Down syndrome, a common cause of mental retardation, have an extra copy of this chromosome. This is notable because the similarities between Alzheimer's and Down syndrome are striking.

People with Down syndrome almost invariably develop Alzheimer's symptoms in middle age, if they live that long. Tiny amyloid deposits begin showing up in their brains during adolescence, some 20 years before the distinctive tangles and plaques appear. Whether the two disorders are genetically related is unclear, but at least one study found that Alzheimer's patients had a higher than expected number of relatives with Down syndrome.

Researchers hope that the discovery of the genetic mutations linked to Alzheimer's will shed new light on why the disease causes brain cells to die, and that this understanding will lead to the development of drugs that can protect these cells.

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Late-onset Alzheimer's disease

One form (or allele) of a gene that directs the manufacture of a protein called apolipoprotein E (ApoE) has been linked to late-onset Alzheimer's. However, that gene doesn't explain all cases. The ApoE gene is located on chromosome 19 and comes in three alleles: E2, E3, and E4.

Everyone has two genes for ApoE, one inherited from each parent. It's possible to have any one of six combinations — either mixed alleles or a matched pair. The E3 allele is the most common; in fact, more than half the population has a double dose of E3. The relatively rare E2 may provide some protection against Alzheimer's disease. E4, the dangerous variant, is carried by 14% of the U.S. population and by as many as 46% of people with Alzheimer's who have a family history of the disease.

Having one E4 allele increases the risk of developing late-onset Alzheimer's (particularly in people ages 60–75) and lowers the age of onset. Having two E4 alleles strengthens these effects. It's not known exactly how the E4 allele works to increase the risk of developing Alzheimer's, but scientists believe it may play a role in the faulty clearing of beta-amyloid deposits from the brain. In theory, the accumulation of beta-amyloid in the brain sets in motion a series of events that leads to the destruction of nerve cells — but exactly why this abnormal protein is overproduced or not cleared efficiently remains a mystery. ApoE also shuttles cholesterol into and out of cells, and people with E4 are at increased risk of cardiovascular disease.

A pattern of family-based inheritance for late-onset Alzheimer's (age 60 or older) has been difficult to establish, so the chances of inheriting a defective gene are unknown. Having the E4 allele is no guarantee that you will develop the disease, and not having the allele is no guarantee that you won't. The E4 allele is a risk factor for — but not a cause of — late-onset Alzheimer's disease. This lead, while establishing that there is some genetic risk for late-onset Alzheimer's disease, provides no basis for testing the ApoE genotype in healthy individuals without dementia. Mutations on other genes believed to affect the risk of developing late-onset Alzheimer's are also being studied.

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Cardiovascular risk factors

Many studies show that physiological conditions that harm the heart and blood vessels also increase the risk of Alzheimer's disease and vascular cognitive impairment. These include high blood pressure, high cholesterol, obesity, and smoking, which all increase the risk of stroke, a direct cause of vascular cognitive impairment. But such risk factors may also indirectly lead to Alzheimer's disease by other means.

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High cholesterol

People with high total cholesterol face increased odds of Alzheimer's disease later in life. A desirable level is less than 200 milligrams of cholesterol per deciliter (mg/dL) of blood. People with cholesterol readings of more than 251 mg/dL during middle age were twice as likely as people with lower cholesterol levels to develop Alzheimer's within 21 years, according to a 2005 study of 1,449 adults published in Archives of Neurology . There is some evidence that statins, a commonly prescribed class of cholesterol-lowering drugs, may reduce the risk of Alzheimer's disease (see "Statins").

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Hypertension

Several studies show that people with high blood pressure are at increased risk of Alzheimer's disease. Blood pressure is considered high if systolic pressure (the first number in a blood pressure reading, taken during the heart's pumping phase) is 140 millimeters of mercury (mm Hg) or more, or if diastolic blood pressure (the second number in the reading, taken during the heart's resting phase) is 90 mm Hg or more. Treating high blood pressure may help prevent Alzheimer's. A 2006 study in Archives of Neurology, which included 3,300 people over age 65, found that those taking any blood pressure medication had a 36% lower risk of developing Alzheimer's disease than those who took none. The greatest risk reduction was in people who were taking diuretics.

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Obesity

Research points to excess weight as a risk factor for Alzheimer's disease and other dementias. People who were obese in middle age were nearly two and a half times as likely to eventually be diagnosed with Alzheimer's disease or another dementia as were people whose weight was normal, according to a 2005 Swedish study in Archives of Neurology . Similar findings, based on an American study involving 9,000 people, were reported at a 2006 meeting of the American Academy of Neurology. Both the Swedish and American teams found that obesity roughly doubled the risk of dementia even when people did not have other risk factors, such as high blood pressure and high cholesterol, that can also increase the likelihood of dementia.

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Smoking

Smoking is a risk factor for cardiovascular disease, so it makes sense that it would also make you vulnerable to Alzheimer's disease and other dementias. Several studies have found a link. A 2005 study published in Neurology, which examined a number of vascular risk factors, found that smoking and diabetes were the ones most strongly linked with developing Alzheimer's disease. Another study, published in Neuroepidemiology in 2006, found that smokers were more than three times as likely to develop Alzheimer's as people who never smoked. However, it is unclear how much people who quit smoking reduce their risk of Alzheimer's.

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Homocysteine

A number of studies have concluded that people with high blood levels of the amino acid homocysteine are at increased risk for heart disease and stroke, so researchers also investigated whether there is a link between homocysteine and dementia. So far, the results have been mixed. A 2002 study published in the New England Journal of Medicine concluded that people who had high homocysteine levels were more likely to develop Alzheimer's disease than those with low levels. In 2005, a study published in Neurology found a significant correlation between high homocysteine and beta-amyloid protein in blood, a possible risk factor for Alzheimer's disease. However, the study found no significant difference in homocysteine levels among people with Alzheimer's disease and a control group. More research is needed to clarify the relationship between homocysteine and Alzheimer's disease.

Homocysteine forms when the body breaks down protein. Then it either accumulates in the body or is recycled with the help of B vitamins. When individuals don't get enough of three B vitamins — folic acid, B₆ , and B₁₂ — homocysteine levels rise.

Thus far, however, no evidence exists that lowering homocysteine will help stave off Alzheimer's disease — or heart disease, for that matter. Even so, it's important to get enough folic acid and vitamins B₆ and B₁₂ , as these vitamins perform a number of vital roles in the body. Many breakfast cereals, pastas, and other grains are now fortified with B vitamins. Green leafy vegetables, citrus fruits and juices, bananas, and dry beans are good choices, too. Also consider taking a multivitamin with 400 micrograms of folic acid, 100 milligrams of vitamin B₆ , and 100 micrograms of B₁₂ .

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Diabetes

People with either type 1 or type 2 diabetes face a greater risk of Alzheimer's disease and vascular cognitive impairment. Research indicates that this increase in risk may be due to a shared mechanism: a deficiency or dysfunction of insulin, the hormone that enables cells in the body to use blood sugar (glucose).

Brain cells need blood sugar in order to function, and in particular to execute a high-energy task such as learning a skill or forming a memory. Yet a 2005 study in the Journal of Alzheimer's Disease provides evidence that the brain's ability to use blood sugar may be compromised as Alzheimer's disease develops. The researchers found that insulin levels and the number of insulin receptors in the brain fall dramatically in the early stage of Alzheimer's disease, and they continue to plummet as the disease progresses. In the advanced stage of Alzheimer's disease, there are 80% fewer insulin receptors in the brain than is normal. The researchers think that the decline in insulin and insulin receptors in the brain may be linked somehow to the death of neurons and appearance of tangles in the brain — the signs of Alzheimer's disease.

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Head injury

Many former boxers develop a condition called dementia pugilistica (boxer's dementia) after suffering repeated blows to the head. The microscopic changes in their brains resemble those in Alzheimer's disease, which led researchers to wonder if brain injury might be a factor in the disease. Researchers discovered amyloid deposits in people who died shortly after severe head injury, especially in those with the ApoE4 gene. The authors concluded that less severe head injuries might trigger amyloid deposits in susceptible people, resulting years later in full-blown Alzheimer's.

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Review Date: 2007-01-01

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