Health Letter, April 2014
By Susan Molchan, M.D.
Dr. Molchan is a geriatric psychiatrist who has worked at the National Institutes of Health (NIH) and the Food and Drug Administration, most recently as Program Director for Biomarkers, Diagnosis and Neuroimaging at the National Institute on Aging, NIH.
Despite their taste for cigarettes and scotch, my grandparents outlived more than 85 percent of their contemporaries when they passed away at ages 82 and 85. Forty-seven percent of those born in the U.S. in 1900, as they were, survived to age 60, and about 13 percent lived to age 80. Today, approximately 88 percent live to age 60, and 57 percent see their 80th birthday.
With longer life comes “the distressing fact that more people … outlive their brains,” noted a former president of the American Psychiatric Association in 1944. Since that time, the number of Americans age 85 and older has increased more than tenfold, and as age is the biggest risk factor for dementia, many in the health care community now refer to the rising numbers of elderly as ominously portending an “epidemic” of dementia.
Today, dementia is increasingly recognized — as most chronic diseases are — as a result of multiple factors. Alzheimer’s disease is considered the most common cause of dementia (see “Diagnosing Dementia” shaded box below), but according to most dementia experts, “the vast majority of dementia cases, especially those occurring late in life, tend to involve a mixture of Alzheimer’s disease, vascular disease, and other degenerative factors.” Leaders in geriatric medicine have noted that “prevention is often the key to better control of epidemics, including epidemics of chronic diseases.”
Prevention is the key
Time marches on, but there are ways we can soften its effects on our brains. Heart-healthy habits — such as controlling blood pressure, cholesterol and weight, as well as maintaining a healthy diet and exercising — have long been associated with lower dementia risk. In higher-income countries, where people are better educated and are adopting healthier lifestyles, dementia rates appear to be decreasing relative to past rates in people of the same age.
Between 1989 and 1994, scientists in the U.K. randomly selected and interviewed 7,635 people age 65 and older. They repeated this process within the same regions with 7,796 people between 2008 and 2011. The researchers found that over this roughly 20-year period, the dementia rate dropped by a robust 24 percent. That is, those in the later group had a lower risk of dementia than those in the earlier group. This finding reinforced the likelihood that decreases in risk factors such as smoking, as well as fewer cholesterol and blood pressure problems, are favorably affecting dementia rates.
Critics of the study noted the lower response rate (more people declining to participate) in the second, later group. However, the authors took this into account when analyzing their data, and their conclusions still held. Dr. Carol Brayne, the study’s primary author, conjectured that many of the older people in the later group declined participation because “they were just too busy” — they led more active lives than people did 20 years ago.
Danish researchers reported similar results after comparing cognitive abilities between a large group of subjects born in 1905, whom they assessed at age 93, with a group born in 1915, whom they assessed at age 95. Those in the later cohort were in cognitively better shape, even though they were two years older when tested.
The seven dementing dangers
Researchers at the University of California, San Francisco (UCSF) looked at data on seven known risk factors for dementia or Alzheimer’s disease (for which these risks were the same): diabetes, midlife high blood pressure, midlife obesity, smoking, depression, low educational attainment and physical inactivity. They estimated how much each factor contributed to dementia risk. (The researchers did not look at diet, as the data on diet did not allow them to formulate reliable estimates.)
The UCSF research team found that these seven factors contributed to about half the cases of Alzheimer’s disease. (See the table below.) They estimated that a 10 to 25 percent reduction in all seven factors could potentially decrease the number of dementia cases by hundreds of thousands in the U.S.
Physical inactivity contributed to the largest number of dementia cases (more than 1.1 million) in the U.S. Inactivity, of course, also is a risk factor for cardiovascular disease and the problems associated with it — high blood pressure, obesity and diabetes. Hence the adage: “What’s good for your heart is good for your brain.”
|Risk Factor||Attributable Risk of Dementia/Alzheimer’s Disease|
|High blood pressure (midlife)||8%|
The second-largest contributor was depression. It has long been hypothesized to be a risk factor for dementia, possibly through increases in the stress hormone cortisol, which is associated with shrinkage in the hippocampus, one of the first regions of the brain involved in Alzheimer’s disease. Depression also is associated with decreased levels of growth factors that help support and nurture nerve cells.
Most of the remaining risk factors for dementia and Alzheimer’s disease involve the usual culprits associated with many dire diseases: smoking, high blood pressure, obesity and diabetes.
Importance of physical activity
Being more fit and physically active throughout life has been associated with reduced risk of dementia in many studies, some of which have shown that the brains of fit people work more effectively.
For example, in one study at the Medical College of Wisconsin, researchers studied the effect of exercise in people with mild cognitive impairment (people with more memory problems than is typical for their age). Mild cognitive impairment increases the likelihood that one will develop dementia, with 40 percent of those in this population declining to the point of being diagnosed with dementia within four years.
The Wisconsin researchers found that moderate exercise (walking on a treadmill for four 30-minute sessions weekly for 12 weeks) improved memory function, as measured by a word recall test. Scans showed that regions of the brain involved in memory and Alzheimer’s disease appeared to work less hard after the exercise program than they did before the exercise program began. They also worked more efficiently, as younger brains do.
Our brains begin to shrink, or atrophy, in our 30s. By age 90, the average brain has shrunk 15 percent. Guess which areas shrivel the most? The frontal and temporal lobes, including the hippocampus, regions especially important for thinking and memory. People who are more fit or more physically active have more brain tissue in those regions, as measured on scans.,,, Exercise literally pumps up the brain volume.
Using the strongest level of evidence in medical research — randomized clinical trials — a team of researchers led by Dr. Arthur Kramer and his colleagues at the University of Illinois Urbana found that older people participating in aerobic exercise for six months to one year bulked up gray matter in regions of the brain involved in memory. These changes were not seen in older people assigned to participate in stretching and muscle-toning sessions. The subjects in the aerobic exercise group also did better on tests of memory and thinking.,
To achieve the cognitive benefits of exercise, you do not have to be a gym rat. Just a moderate level of exercise is all it takes to benefit brain function and to reduce risk of Alzheimer’s disease and dementia in general. In most of the studies, the tested exercise was walking.
People with mild cognitive impairment also have shown improved memory function after regular resistance training (lifting weights) — for intervals such as twice a week for six months — doing two sets of six to eight repetitions of exercises targeting large muscle groups.
Consensus is growing that just as for physical health, a variety of activities and exercises is probably best for cognitive health. According to the Centers for Disease Control and Prevention, all adults should get at least 150 minutes of moderate-intensity aerobic activity each week (such as 20-25 minutes of brisk walking daily). Studies to date suggest that for brain benefits, at least 30 minutes of exercise daily, or close to daily, is needed.
The cognitive benefits of exercise do not appear to have an age limit. For example, in a study that followed more than 1,200 women age 85 or older for five years, the one-third who were most active had a significantly lower risk of dementia compared to the one-third who were least active (13 percent versus 23 percent).
If anything comes close to a fountain of youth, it is exercise. It may support brain health through many mechanisms — for example, by increasing blood flow to the brain and encouraging new nerve cell growth. From animal studies, we know that exercise actually lengthens nerve cell fibers called dendrites and promotes the formation of intricate branches that connect with many other nerve cells.,
A number of clinical trials are underway to assess whether exercise can actually decrease Alzheimer’s disease or dementia incidence or delay the onset of dementia in people with mild cognitive impairment.
Education levels and dementia
As seen in an increasing number of studies, the UCSF researchers reported that a low level of education increased the risk for dementia. They estimated that 7 percent of Alzheimer’s disease or dementia cases were associated with this risk factor. Other studies have demonstrated that the more years of education a person has, the more protection one has from dementia. These findings suggest that individuals with more education may develop cognitive reserve that helps delay the onset of dementia.,
The concept of cognitive reserve for the brain can be likened to protection for the body after a fall by bones and muscles thickened and strengthened by exercise. All a person learns and experiences can fortify the brain’s gray matter in old age. Many researchers think that cognitive reserve explains why some people can have brains burdened by plenty of amyloid deposits and neurofibrillary tangles typical of Alzheimer’s disease but do not appear to have problems with their memories. They can function normally for longer periods of time.,
Still, if you didn’t finish high school, don’t despair! The grade level one has completed is simply one objective, convenient way for researchers to quantify a particular variable, always important in science, in this case to estimate cognitive reserve. Other measures also have been associated with lower dementia risk, including occupational attainment, IQ and engagement in mentally stimulating activities.
The bottom line is that staying mentally and socially engaged in stimulating, challenging activities over a lifetime is important. As with physical exercise, it is best to mix it up, or cross-train, to challenge the brain, so try new things.
There are now many brain-training programs and mobile apps featuring games and exercises that manufacturers claim will improve your memory and brain function in general. There is no evidence that such training makes you better at anything besides the games themselves — and much less proof that they lower dementia risk.,, The games are simply a different type of mental activity; they certainly cannot hurt, especially if one enjoys doing them. However, for baby boomers and those younger, who likely spend too much of their lives planted in front of computers, it is likely better to take a hike, go for a swim or visit the gym.
The genetics link
A few hundred extended families in the world carry one of three mutated genes that affect amyloid protein in the brain and guarantee that Alzheimer’s disease will afflict them, generally before the age of 65. The population having these genes accounts for less than 5 percent of cases of Alzheimer’s disease.
The best-known genetic risk factor for late-onset Alzheimer’s disease in the general population relates to a protein in blood that binds and transports cholesterol. The protein comes in three varieties: apolipoprotein E2, E3 and E4.
People who have the gene for the E4 form of apolipoprotein have an increased risk of Alzheimer’s disease. This risk is increased as much as tenfold if someone has two copies of this gene: one from mom and one from dad. (The gene also is a risk factor for heart disease.)
Apolipoprotein E4 gene carriers are by no means guaranteed to be afflicted with Alzheimer’s disease, unlike people with the previously mentioned gene mutations that affect amyloid protein. They just have increased risk for developing the disease. Most people carry the apolipoprotein E3 gene type (60 percent), and approximately 14 percent carry the E4 gene type, with 2 percent carrying two copies.
The E2 gene type is slightly protective against Alzheimer’s disease. About 11 percent of people have one copy of it, and 0.5 percent have two copies.
Drug treatment for Alzheimer’s disease
There are currently four drugs prescribed to treat Alzheimer’s disease. Three of them are known as cholinesterase inhibitors (the most commonly used is donepezil, brand name Aricept), and the other is memantine (brand name Namenda). Although there is evidence that some patients have slight improvements with these drugs that are statistically significant, the real-world effects of these drugs are marginal. Families and caregivers generally cannot tell the difference in affected loved ones between taking these drugs and taking a placebo. The drugs also have significant side effects.
The next round of drugs that pharmaceutical companies currently are developing do not look much more promising. They target amyloid, the protein found in the plaques that build up in the brains of people with Alzheimer’s disease and other disorders (this buildup also occurs with normal aging). Research on amyloid as a treatment target has dominated the Alzheimer’s field for the past 20 years, although some scientists worry that too many resources have been poured into this area to the exclusion of other promising leads.,
So far, clinical trials targeting amyloid have failed. Some scientists speculate that these failures occurred because the drugs were given too late in the disease process. However, other researchers think amyloid helps nerve cells communicate and survive and that amyloid, far from being a cause of Alzheimer’s disease, is a beneficial reaction of brain cells to the disease.
The next push for the supporters of the amyloid theory is to test the drugs earlier in the disease process, especially in families with mutations of amyloid genes. Indeed, this will be a very important test of the amyloid theory. But even if the drugs help members of these families who develop dementia at a young age, it does not necessarily mean it will help the vast majority of dementia cases: people who are older than 80 and have many factors contributing to their decline.
Alzheimer’s disease is considered the cause of dementia in about 70 percent of those older than 65. Vascular or blood vessel disease, such as stroke, causes about 10 to 20 percent. Another 10 to 20 percent is caused by Lewy body dementia, named after bits of protein found in degenerating brain cells. (Clinically, this condition looks a lot like Parkinson’s disease.) The only definitive way to confirm whether a patient had one of these diseases is to conduct an autopsy and view slices of the brain under the microscope — looking for pathological changes seen with each type of dementia. Often, doctors and researchers find that the brain abnormalities overlap among these three most common dementia types.
Image: Alila Medical Media/Shutterstock.com
When someone complaining of memory problems visits a doctor, a diagnosis is primarily made by listening to the story of the patient’s symptoms, along with conducting tests of memory and other aspects of thinking. The doctor evaluates medical and family history, along with physical signs, such as tremor. The goal of this evaluation is to identify any potentially treatable causes of the memory problems, such as high blood pressure; diabetes; drug effects, including those related to alcohol use; sleep apnea; depression; or low levels of vitamin B12 or thyroid hormone in the blood. Usually as part of a routine evaluation for dementia, a patient’s brain is scanned using computed tomography or MRI to rule out a brain tumor, strokes or injury.
Once other causes of dementia are ruled out, the patient is considered likely to have Alzheimer’s disease.
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