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A Guide to Alzheimer's Disease

Dear Reader,

Did you ever stride purposefully into a room, stand in one spot, and then wonder what you'd intended to do? Lose your house keys or forget where you parked the car? Relax. Occasional memory slips are natural.

Perhaps, though, memory problems are piling up in ways that affect daily life. Or maybe your concerns go beyond forgetfulness. Do you find yourself struggling to follow a conversation or find the right word, becoming confused in new places, or botching tasks that once came easily? Everyone has these experiences sometimes, but if they frequently happen to you or someone you love, they may be early signs of Alzheimer's disease.

This condition strikes fear into people's hearts, with good reason. It is the leading cause of dementia, a brain disorder that robs people of the ability to think, learn, and remember, and, eventually, of their very selves. About 5.4 million Americans have Alzheimer's disease, and estimates suggest it will affect 7.7 million by 2030. Already, it is the sixth leading cause of death in the United States. There is no cure, and available treatments alleviate symptoms temporarily at best.

Better times may be coming. Many new drugs are under investigation. New research is turning up evidence of very early signs of Alzheimer's, offering possible targets for new treatments that could alter the disease's course before more flagrant symptoms appear. And diagnostic guidelines published in 2011 by the National Institute on Aging and the Alzheimer's Association aim to help researchers move closer to early detection and intervention.

Meanwhile, caring for someone with Alzheimer's continues to be one of the toughest jobs in the world. It is stressful, physically and emotionally draining, and very expensive, as almost 15 million unpaid caregivers for people with Alzheimer's and other dementias can attest.

Because the disease is progressive, coping with it requires foresight and careful advance planning. People in the early stages of Alzheimer's often can be partners in that planning, and this comprehensive report can guide you, as well. In it, you'll find hope for people who are struggling with Alzheimer's and practical help for caregivers.

With forethought, patience, knowledge, and support, you can better meet the challenges posed by this disease and improve the quality of your life and that of your loved ones.

Sincerely,

John H. Growdon, M.D.
Medical Editor

Risk factors for Alzheimer's disease

A number of factors raise or lower risk of developing Alzheimer's disease. Some of these you can't control (such as age, gender, and family history); others you can influence (such as cholesterol levels, smoking, and weight).

Age and gender

Your age alone poses some risk. Yet while risk usually rises after age 65 and continues to increase as you get older, Alzheimer's is not an inevitable consequence of aging.

If you look at numbers only, women appear to have a higher rate of Alzheimer's disease than men do (see Figure 5). Almost two-thirds of Americans who have Alzheimer's disease are female. Women who live to age 65 have a one-in-five chance of developing Alzheimer's disease in their remaining lifetime. For men, the risk is one in 10. However, experts believe this difference reflects women's greater longevity.

Figure 5: Alzheimer's and gender

Alzheimer's and gender

Of the 5.2 million people over age 65 with Alzheimer's in the United States, 3.4 million are women and 1.8 million are men.

Family history and genetic factors

When a family member has Alzheimer's, people often wonder about their own chances of developing the disease. Family history is indeed a risk factor for Alzheimer's. If you have a parent or sibling with Alzheimer's, you're more likely to develop the disease than someone who does not have a first-degree relative with this condition. Risk rises further if you have more than one first-degree relative with Alzheimer's. But while heredity is a major factor in a small number of families, for most people, genetics seem to play only a minor role or none at all. As scientists continue to mine new research on genes associated with late-onset Alzheimer's, though, our current understanding may shift.

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. Excessive amounts of beta-amyloid fragments are thought to be toxic to nerve cells.

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.

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 (diagnosed at age 60 or older). 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 to 75) and lowers the age of onset. Having two E4 alleles strengthens these effects. Keep in mind, though, neither situation guarantees that you'll develop Alzheimer's disease, any more than having no E4 allele guarantees that you won't. Scientists believe the E4 allele 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 also at increased risk of cardiovascular disease.

Ever larger studies are delving deeper into genetic links. So-called genome-wide association studies look for possible genetic links to a disease by searching through DNA on all of the chromosomes in a specific population of people, such as Alzheimer's patients. These studies have turned up gene variants named CR1, CLU, and PICALM, which increase susceptibility for Alzheimer's in people of European ancestry. Research published in Archives of Neurology in 2010 suggests that PICALM increases risk primarily in people with the E4 allele.

In two large studies analyzing genes of well over 50,000 Americans and Europeans, reported in Nature Genetics in 2011, researchers found five new genes that make Alzheimer's more likely to occur in the elderly. This groundbreaking study doubled the number of genes known to play a role in Alzheimer's disease, casting more light on the biological underpinnings of the disorder. Intriguingly, some of the new genes are linked to cholesterol and inflammation, which have been implicated as potential contributory factors in Alzheimer's. However, compared with the ApoE gene, each of the new genes increases risk only modestly.

Other health problems

Many studies show that physiological conditions that harm the heart and blood vessels also increase the risk of Alzheimer's disease and vascular dementia. These include high blood pressure, high cholesterol, obesity, and smoking, which all increase the risk of stroke, a direct cause of dementia. But such risk factors may also indirectly lead to Alzheimer's disease by other means. Many of these risk factors are also common in people with diabetes — yet another condition linked to Alzheimer's disease. Most of these factors can be controlled by lifestyle changes, either alone or with medications.

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 in some populations (see "Cholesterol-lowering drugs"). Consistent with this research, a 2011 study published in Nature Genetics found that genes that influence Alzheimer's risk in the elderly tend to be involved with cholesterol and inflammation.

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) is 140 millimeters of mercury (mm Hg) or more, or if diastolic blood pressure (the second number in the reading) is 90 mm Hg or more. Treating high blood pressure may help prevent Alzheimer's. A 2006 study, 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. A more recent study in BMJ linked a class of hypertension drugs called angiotensin-receptor blockers with a significant decrease in the risk of Alzheimer's disease and dementia; the effect was seen mostly among men.

Obesity

Research points to excess weight as a risk factor for Alzheimer's disease and other dementias. A 2007 study that tracked more than 10,000 people for an average of 36 years revealed the potential magnitude of this risk: people who were overweight in midlife were twice as likely to develop Alzheimer's disease later in life, and people who were obese had a threefold higher risk of the disease. The findings, published in Current Alzheimer Research, were adjusted to account for possible confounding factors, such as smoking, high blood pressure, heart disease, and other illnesses.

In keeping with those findings, a 2010 study published in Neurobiology of Aging found that a higher body mass index (see Table 2) was associated with lower brain volume among patients with mild cognitive impairment and Alzheimer's disease even after the researchers accounted for age, gender, and level of completed education.

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. A 2007 review pooling results from 19 different studies estimated that elderly smokers faced a nearly 80% higher risk of Alzheimer's disease than those who had never smoked.

However, it is unclear how much quitting smoking reduces your risk of Alzheimer's. At least one study found inconsistent links between smoking history and cognitive decline, perhaps due to the difficulty of tracking and testing former smokers. Another — a 2010 study in Archives of Internal Medicine — found that among a sample of over 21,000 people, those who smoked more than two packs of cigarettes a day at midlife had more than double the risk of developing dementia in old age when compared with nonsmokers. However, people who had stopped smoking by midlife and those who smoked less than half a pack a day had a risk of dementia similar to that of people who had never smoked.

Diabetes

People with either type 1 or type 2 diabetes face a greater risk of Alzheimer's disease and vascular dementia. In fact, type 2 diabetes, which is often linked to obesity and lack of activity, appears to double or triple the odds of developing Alzheimer's disease. 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. A study in TheJournal 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. Researchers are continuing to study the association between insulin signaling to the brain and cognitive function.

Head injury

Boxers suffer repeated blows to the head in the course of their careers. Years later, many develop what was once known as dementia pugilistica (boxer's dementia), a condition since renamed chronic traumatic encephalopathy (CTE). Among its symptoms are memory problems and marked shifts in behavior and personality. The microscopic changes seen in the brain consist mainly of neurofibrillary tangles, much like those seen in Alzheimer's disease. Similar lesions have now been identified in some athletes who sustain multiple, even if mild, concussions, such as football players.

CTE continues to worsen for decades after boxers and other athletes stop engaging in the sports activities that caused repetitive trauma. Apparently, the harm done to the brain continues long after the injuries occurred, as a variety of natural substances are released and troubling responses — for example, inflammation or a breach to the blood-brain barrier (a filter, created by tightly packed endothelial cells in a network of capillaries in the brain, that prevents potentially harmful materials in the blood from entering the brain) — trip off a cascade of further consequences.

Similarities between CTE and Alzheimer's disease led researchers to wonder if head injuries, such as those sustained by boxers, football players, and some combat veterans, might be a factor in Alzheimer's disease. And indeed, moderate head injury leading to loss of consciousness or amnesia for more than half an hour doubles the odds of developing Alzheimer's later in life, while a severe injury that causes either problem for more than 24 hours increases the risk 4.5 times. Preliminary evidence indicates that having the ApoE E4 allele and experiencing repeated concussions raises risk for CTE.

While scientists are just beginning to trace these connections, particularly where milder head injuries are concerned, you needn't wait for all the evidence to come in. Protecting your brain is common sense. The Alzheimer's Association recommends buckling your seat belt, wearing a helmet during sports, and "fall-proofing" your home. Allowing a doctor to evaluate any concussion and decide when it's safe to return to sports and other activities is important, too.

Author: Harvard Health Publications
Date Last Reviewed: 10/1/2011
Date Last Modified: 9/23/2013
Copyright Harvard Health Publications