Preventing dementia: Diet & exercise

A study¹ of nearly 2000 older adults has found that eating a Mediterranean diet was associated with less risk of developing mild cognitive impairment or of transitioning from MCI to Alzheimer's disease. The third with the highest scores for Mediterranean diet adherence had a 28% lower risk of developing MCI compared to the third with the lowest scores, and of those who already had MCI, those with the highest scores for Mediterranean diet adherence had a 48% less chance of developing Alzheimer’s.

Another, similar-sized study², has found that those who adhered more strongly to a Mediterranean-type diet had a 40% risk reduction, and those who were very physically active had a 33% risk reduction of Alzheimer's -- doing both gave people a 60% reduction.

A Mediterranean-type diet is typically characterized by high intake of fish, vegetables, legumes, fruits, cereals and monounsaturated fatty acids; relatively low intake of dairy products, meats and saturated fats; and moderate alcohol consumption. Most of these components have been independently associated with reduced dementia risk. Let's look at them one by one.

Fruit & vegetables

A very large study³ of older adults found that those who ate fruits and vegetables daily reduced their risk of dementia by 30% compared to those who didn’t regularly eat fruits and vegetables. Another large, long-running epidemiological study⁴ found that those who drank three or more servings of fruit and vegetable juices per week had a 76% lower risk of developing Alzheimer’s disease than those who drank juice less than once a week. The benefit seemed greatest for those who carried the so-called “Alzheimer’s gene”.

This may not have anything to do with vitamin C. A five-year study⁵ involving nearly 3000 people has found that use of Vitamin C or E or both was not associated with a reduced risk of developing dementia or Alzheimer’s. However a study⁶ involving 4,740 elderly found the greatest reduction in both prevalence and incidence of Alzheimer's in those who used individual vitamin E and C supplements in combination. There was no significant benefit in these vitamins alone.

Of course, it is now well understood that taking vitamins as supplements is not the same as receiving them in food.

Two studies have come out in favor of a diet rich in foods containing vitamin E to help protect against Alzheimer's disease. One study⁷ involved 815 Chicago residents age 65 and older with no initial symptoms of mental decline, who were questioned about their eating habits and followed for an average of about four years. When factors like age and education were taken into account, those eating the most vitamin E-rich foods had a lower risk of developing Alzheimer’s, provided they did not have the ApoE e4 allele. This was not true when vitamin E was taken as a supplement. The effect of vitamin C was not statistically significant.

The other study⁸ involved 5,395 people in the Netherlands age 55 and older who were followed for an average of six years. Those with high intakes of vitamins E and C were less likely to become afflicted with Alzheimer's, regardless of whether they had the gene variation. This association was most pronounced for current smokers.

So beneficial effects of these vitamins may depend on genetics, smoking history, and possibly other lifestyle factors. But there are other valuable compounds common in fruits & vegetables. Another class of antioxidant chemicals, polyphenols, are now suspected. Polyphenols generally exist primarily in the skins of fruits and vegetables and are particularly abundant in teas, juices and wines.

A cell study⁹ also found that quercetin (a flavonoid with greater antioxidant and anticancer properties than vitamin C) protects against cellular damage. Quercetin is particularly abundant in apples (mainly in the skin, and especially the red ones). Other good sources are onions, blueberries and cranberries.

Another cell study¹⁰ found that compounds in blackcurrants (anthocyanins as well as polyphenols) strongly protect neuronal cells against the effects of amyloid-beta. Boysenberries contain the same compounds, and those that are darker are likely to be more potent.

The inconsistent findings regarding vitamins C and E may also have to do with the presence of folates. Data from the Baltimore Longitudinal Study of Aging¹¹ revealed that although those with higher intake of folates, vitamin E and vitamin B6 had a lower risk of developing Alzheimer’s, statistical analysis showed it was only folate consumption that was significant. Those who had at least 400mcg of folates a day (the recommended daily allowance) had a 55% reduction in risk of developing Alzheimer’s. Unfortunately, most people who reached that level did so by taking supplements, suggesting the difficulty of doing so through diet alone.

Folates are abundant in foods such as liver, kidneys, yeast, fruits (like bananas and oranges), leafy vegetables, whole-wheat bread, lima beans, eggs and milk; however, they are often destroyed by cooking or processing.

The benefits of folates probably has to do with its effect on homocysteine. A mouse study¹² indicates that increased levels of homocysteine are produced by low intake of folate and B vitamins, and impair cognition through microvascular changes. 

High levels of homocysteine are associated not only with deficiencies in vitamin B12 and folate, but also with smoking.

High levels of homocysteine were associated in one study¹³ with a more than five-fold increase in the risk for stroke, a nearly five-fold risk for vascular dementia, and almost triple the risk for Alzheimer's disease. Findings from the long-running Framingham study¹⁴ found people with elevated levels of homocysteine in the blood had nearly double the risk of later developing Alzheimer’s disease.

Moreover, evidence from a study¹⁵ using genetically engineered mice suggests that increased levels of homocysteine in the brain cause damage to nerve cells in the hippocampus -- which can be repaired when there is an adequate amount of folate, but not when there is a deficiency.

Omega-3 oils & fish

One of the clearest findings in this area has been the benefits of regularly consuming omega-3 oils, fish oil, and fish. Several epidemiological studies have indicated that regularly eating fish (at least once a week) reduces risk of dementia. More recently, two very large studies have come out in support. One very large study³ of older adults found that those who regularly consumed omega-3 rich oils, such as canola oil, flaxseed oil and walnut oil, reduced their risk of dementia by 60% compared to people who did not regularly consume such oils. Additionally, those who ate fish at least once a week had a 40% lower risk of dementia -- but only if they did not carry ApoE4 gene.

Moreover, for those who didn’t have the gene, regular use of omega-6 rich oils, but not omega-3 rich oils or fish, were twice as likely to develop dementia compared to those who didn’t eat omega-6 rich oils (e.g., sunflower or grape seed oil).

The second study¹⁶ comes from the famous long-running Framingham Heart Study, which found that those with the highest levels of DHA (an omega-3 polyunsaturated fatty acid found in relatively high concentrations in cold-water fish) had a 47% lower risk of developing dementia. Those with these levels tended to eat an average three fish servings a week, as well as an average of .18 grams of DHA a day. Those at lower levels ate markedly less fish.

There is also some suggestion that omega-3 oils might help slow the progression of dementia. A Swedish study¹⁷ found that, although fatty acids DHA and EPA didn't slow cognitive decline in those with mild-to-moderate Alzheimer’s, they did slow decline in those with very mild cognitive impairment (a frequent precursor of dementia). It's been suggested that anti-inflammatory effects are an important reason for the benefit, why might explain why benefits only occur in the very early stages, when levels of inflammation seem to be higher.

Similar results were more recently reported¹⁸ from a large 18-month trial. This one, however, suggested that genetic status might be a factor -- that those without the “Alzheimer’s gene” ApoE4 might benefit even if impairment had progressed to mild-to-moderate Alzheimer’s.

There are a number of reasons why DHA might help brains.

A study involving genetically engineered mice¹⁹ has found that a diet high in DHA dramatically slowed the progression of Alzheimer's by cutting the harmful brain plaques that mark the disease. An earlier study²⁰ showed that DHA protected against damage to the synaptic areas where brain cells communicate and enabled mice to perform better on memory tests. More recent research²¹ has revealed that DHA increases the production of LR11, a protein that is found at reduced levels in Alzheimer's patients and which is known to destroy the protein that forms the plaques associated with the disease.

Food sources of omega-3 fatty acids include fish such as salmon, halibut, mackerel and sardines, as well as almonds, walnuts, soy, flaxseed, and DHA-enriched eggs. These fish have high levels of DHA because they consume DHA-rich algae. Because these fishes' oiliness makes them absorb more mercury, dioxin, PCP and other metals, a less risky yet more costly strategy is to consume fish oil or purified DHA supplements made from algae.

Possible benefits of wine, tea, and coffee

There have been a number of reports that moderate alcohol consumption (generally defined as 1 drink or less per day for women and 1-2 drinks or less per day for men) may help reduce your risk of developing dementia, and a 2008 review of 44 studies²² supported this conclusion. 

However, given that alcohol has known negative effects on the brain, no one is recommending that non-drinkers take up the habit! All one can say is that there's no reason to alter your habits if you are a moderate drinker. On the other hand, if you drink more than this, you are probably best to knock it back to this level.

However, the evidence suggests that it is wine rather than alcohol in general that is beneficial for the brain. A large Danish study²³ found that those who drank wine occasionally in the 1970s had a lower risk of developing dementia in the 1990s (when participants were 65 or older). However, occasional beer drinking was associated with an increased risk of developing dementia. But we cannot draw too hard & fast a conclusion from this, as eating habits were not investigated, and research suggests that wine drinkers may have better dietary habits than beer and liquor drinkers. Moreover, a very large study of older adults³, that found a significant effect of some dietary factors, found no effect of wine.

There are, however, some good reasons for believing regular drinking of red wine may help the aging brain. Red grapes contain several polyphenols that have been shown to significantly reduce cognitive deterioration in genetically engineered mice, by preventing the formation of amyloid beta. One of these is resveratrol; the others are catechin and epicatechin. Resveratrol was much vaunted when its effects were first discovered, but unfortunately it requires extremely high doses. The more recent discovery²⁴ of the catechins is much more exciting, as they appear to be effective at much lower doses. The catechins are also abundant in tea and cocoa.

Tea, most particularly green tea, has also been found²⁵ to inhibit the activity of enzymes associated with the development of Alzheimer's Disease. Green tea also obstructed the activity of beta-secretase.

These inhibitory properties were not found in coffee. However, a large, long-running Finnish study²⁶ has found that those who were coffee drinkers at midlife had lower risk for dementia and Alzheimer’s later in life compared to those drinking no or only little coffee midlife. The lowest risk was found among moderate coffee drinkers (drinking 3-5 cups of coffee/day).

Restricting your calories

There has been some talk that calorie-restricted diets might help prevent Alzheimer's. So far, the only indications have come from experiments with genetically engineered mice. While there have been a number of studies providing evidence that high cholesterol, obesity, and other cardiovascular risk factors increase the likelihood of Alzheimer’s, it is decidedly premature to say whether calorie-restricted diets would benefit humans. Particularly since one of the early signs of Alzheimer's is weight loss. So it is certainly not recommended that people severely restrict their diets. More useful is removing certain food types (e.g., the "bad" oils; sugar -- there is some evidence that Alzheimer's may be a type of diabetes), and increasing consumption of others (fish, "good" oils, fruit & vegetables).

There may also be a genetic link. A four-year study²⁷ of nearly 1000 older adults found that among those who carried the ApoE e4 gene, those who consumed the most calories had a 2.3 times greater chance of developing Alzheimer’s compared to those who ate the fewest calories. But calories weren't a factor for those without the gene.

Cholesterol

A study²⁸ involving nearly 10,000 people who underwent health evaluations between 1964 and 1973 when they were between the ages of 40 and 45, has found that those with total cholesterol levels between 249 and 500 milligrams were one-and-a-half times more likely to develop Alzheimer's disease than those people with cholesterol levels of less than 198 milligrams. People with total cholesterol levels of 221 to 248 milligrams were more than one-and-a-quarter times more likely to develop Alzheimer's disease. High cholesterol increased risk regardless of midlife diabetes, high blood pressure, obesity, smoking and late-life stroke.

A review²⁹ of autopsy cases of patients over 40 years old found that high blood cholesterol levels were correlated with the presence of amyloid deposits in the brain in the youngest subjects (aged 40-55).

An analysis³⁰ of data on 1037 older women who had participated in a clinical trial of hormone replacement therapy found that high cholesterol levels increase the risk of cognitive impairment.

A large-scale Finnish study³¹ following 1449 men and women over 21 years found that raised systolic blood pressure and high serum cholesterol concentration, particularly in combination, in midlife, increase the risk of Alzheimer's disease in later life. Raised diastolic blood pressure had no significant effect.

However, the long-running, large-scale Framingham Heart study³² found that, after adjustment for age, sex, APOE genotype, smoking, body mass index, coronary heart disease, and diabetes, there was no significant association between AD risk and cholesterol level.

Previous studies suggesting that fat may be involved in the development of dementia and Alzheimer’s disease have been contradicted by a new study³³ involving over 5,000 elderly people over a period of six years. The study found no correlation between fat and cholesterol intake and risk of dementia, and no evidence for a reduction in risk for those taking cholesterol lowering medication.

A cell study³⁴ provides more understanding of why there might be a link between cholesterol and Alzheimer's disease. The study found that proteins which help control cholesterol levels in arterial walls were also present in neurons, and when the genes for these proteins were over-expressed, production of amyloid beta protein fell. The finding suggests a new approach to slowing Alzheimer’s. The study also showed that the apoE protein is extremely good at regulating cholesterol removal from neurons — the gene for this protein is a well-known genetic risk factor for Alzheimer's.

Diabetes

A large Swedish study³⁵ has found that men with low insulin secretion capacity at age 50 were nearly one-and-a-half times more likely to develop Alzheimer’s disease than men without insulin problems. The risk was strongest in those who didn't have the APOE4 gene. Another large study³⁶ found that diabetes was related to a significantly higher risk of developing amnestic mild cognitive impairment in older seniors (average age 76), after controlling for other risk factors. And a large study³⁷ of post-menopausal women (mean age 67 years) found that those with poor blood sugar control were four times more likely to develop MCI or dementia. Findings³⁸ from the long-running Religious Orders Study also support a link between diabetes and an increased risk of developing Alzheimer's disease.

Evidence from a mouse study³⁹ suggests that diabetes might increase risk because elevated blood glucose levels interact with beta amyloid in a way damaging to blood vessels in the brain. In fact it has been suggested that Alzheimer’s could be considered a third form of diabetes. Another study⁴⁰ provides evidence that amyloid oligomers remove insulin receptors from nerve cells, rendering those neurons insulin resistant. Another mouse study⁴¹ suggests that low levels of insulysin, an enzyme that degrades insulin, are a factor. The enzyme, it seems, also degrades amyloid-beta peptides, and even a partial decrease in insulysin activity was found to raise amyloid-beta peptide levels in the brain.

Obesity

A review⁴² of 10 international studies published since 1995, covering just over 37,000 people, has found that obesity increased the relative risk of dementia by an average of 42% compared with normal weight. Being underweight increased the risk by 36%. For Alzheimer's Disease and vascular dementia, specifically, obesity was an even more significant risk: 80% and 73%, respectively. With regards to Alzheimer’s, obesity was more likely to be a risk factor for women, but men were more affected when it came to vascular dementia.

A very large study⁴³ that measured abdominal fat at age 40 to 45 and dementia occurrence some 36 years later, found that those with the highest amount of abdominal fat were nearly three times more likely to develop dementia than those with the lowest amount of abdominal fat. Having a large abdomen increased the risk of dementia regardless of overall weight and existing health conditions, although being obese as well did increase the risk. Those more likely to have abdominal obesity, were women, non-whites, smokers, people with high blood pressure, high cholesterol or diabetes, and those with less than a high school level of education. And another large study⁴⁴ found that those who at 40 were obese, or had high blood pressure, or high cholesterol levels, were twice as more likely to develop dementia by the age of 60. Having all three of these risk factors increased their chances six-fold.

And just to be really scary, when⁴⁵ genetically engineered mice were fed a diet rich in fat, sugar and cholesterol for a mere nine months (although that is, of course, much longer for a mouse than it is for us!), they developed a preliminary stage of Alzheimer's pathology in their brains, suggesting that a ‘fast food’ diet could be a contributory factor in those with the Alzheimer’s gene.

Physical exercise & fitness

A number of studies have found that physical fitness reduces the risk of dementia. One way physical exercise can help fight dementia is through its ability to grow neurons in the hippocampus. This is well-established in rodent studies, and has been confirmed in small human studies. One such study⁴⁶ found the association between physical fitness and hippocampus size was specifically associated with performance on certain spatial memory tests. Another⁴⁷ found that those with early Alzheimer's disease who were less physically fit had four times more brain shrinkage when compared to normal older adults than those who were more physically fit, suggesting the value of physical fitness extends to slowing down the progression of the disease.

Another reason for exercise to prevent dementia is through its effect on cardiovascular fitness, and a reasonably large four-year study⁴⁸ did indeed find that the most active (top third) were significantly less likely to develop vascular dementia than the least active (bottom third). Interestingly, no such association was found with Alzheimer’s disease. However, at least two large studies have found a significantly reduced risk of dementia in those who had higher levels of fitness⁴⁹ or exercised three or more times a week⁵⁰. It may be that exercise has a greater effect on vascular dementia, but many cases of Alzheimer's dementia are actually mixed dementia, with a vascular component.