exercise

Total Cognitive Burden

Because it holds some personal resonance for me, my recent round-up of genetic news called to mind food allergies. Now food allergies can be tricky beasts to diagnose, and the reason is, they’re interactive. Maybe you can eat a food one day and everything’s fine; another day, you break out in hives. This is not simply a matter of the amount you have eaten, the situation is more complex than that.

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Physical activity & older adults

Because physical activity is important for preventing cognitive decline and dementia in older adults (see my article on physical activity and cognition and my article on helping prevent dementia through diet & exercise), and especially because I'm a sucker for infographics, I wanted to share with you this infographic on physical activity & older Americans from Evergreen Rehabilitation:

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The value of intensive practice

Let’s talk about the cognitive benefits of learning and using another language.

In a recent news report, I talked about the finding that intensive learning of a very novel language significantly grew several brain regions, of which two were positively associated with language proficiency. These regions were the right hippocampus and the left superior temporal gyrus. Growth of the first of these probably reflects the learning of a great many new words, and the second may reflect heavy use of the phonological loop (a part of working memory).

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Preventing dementia: Diet & exercise

It's increasingly clear that eating a healthy diet can have a big impact on whether or not you develop dementia.

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.

References: 

  1. Scarmeas, N. et al. 2009. Mediterranean Diet and Mild Cognitive Impairment. Archives of Neurology, 66(2), 216-225.
  2. Scarmeas, N. et al. 2009. Physical Activity, Diet, and Risk of Alzheimer Disease. Journal of the American Medical Association, 302(6), 627-637.
  3. Barberger-Gateau, P. et al. 2007. Dietary patterns and risk of dementia: The Three-City cohort study. Neurology, 69, 1921-1930.
  4. Dai, Q. et al. 2006. Fruit and Vegetable Juices and Alzheimer's Disease: The Kame Project. The American Journal of Medicine, 119 (9), 751-759
  5. Gray, S.L. et al. 2008. Antioxidant Vitamin Supplement Use and Risk of Dementia or Alzheimer's Disease in Older Adults. Journal of the American Geriatrics Society, 56 (2), 291–295.
  6. Zandi, P.P., Anthony, J.C., Khachaturian, A.S., Stone, S.V., Gustafson, D., Tschanz, J.T., Norton, M.C., Welsh-Bohmer, K.A. & Breitner, J.C.S. 2004. Reduced Risk of Alzheimer Disease in Users of Antioxidant Vitamin Supplements: The Cache County Study. Archives of Neurology, 61, 82-88.
  7. Engelhart, M.J., Geerlings, M.I., Ruitenberg, A., van Swieten, J.C., Hofman, A., Witteman, J.C.M. & Breteler, M.M.B. 2002. Dietary Intake of Antioxidants and Risk of Alzheimer Disease. JAMA, 287, 3223-3229.
  8. Morris, M.C., Evans, D.A., Bienias, J.L., Tangney, C.C., Bennett, D.A., Aggarwal, N., Wilson, R.S. & Scherr, P.A. 2002. Dietary Intake of Antioxidant Nutrients and the Risk of Incident Alzheimer Disease in a Biracial Community Study. JAMA, 287, 3230-3237.
  9. Heo, H.J. & Lee, C.Y. 2004. Protective Effects of Quercetin and Vitamin C against Oxidative Stress-Induced Neurodegeneration. Journal of Agricultural and Food Chemistry, 52 (25), 7514–7517.
  10. Ghosh, D., McGhie, T.K., Zhang, J., Adaim, A. & Skinner, M. 2006. Effects of anthocyanins and other phenolics of boysenberry and blackcurrant as inhibitors of oxidative stress and damage to cellular DNA in SH-SY5Y and HL-60 cells. Journal of the Science of Food and Agriculture, in press.
  11. Corrada, M.M., Kawas,C.H., Hallfrisch,J., Muller,D. & Brookmeyer,R. Reduced risk of Alzheimer’s disease with high folate intake: The Baltimore Longitudinal Study of Aging. Alzheimer’s & Dementia, 1 (1), 11-18.
  12. Troen, A.M. et al. 2008. B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice. Proceedings of the National Academy of Sciences, 105, 12474-12479.
  13. McIlroy, S.P., Dynan, K.B., Lawson, J.T., Patterson, C.C. & Passmore, A.P. 2002. Moderately Elevated Plasma Homocysteine, Methylenetetrahydrofolate Reductase Genotype, and Risk for Stroke, Vascular Dementia, and Alzheimer Disease in Northern Ireland. Stroke, 33, 2351–2356.
  14. Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H., D'Agostino, R.B., Wilson, P.W.F. & Wolf, P.A. 2002. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. The New England Journal of Medicine, 346, 476-483.
  15. Kruman, I.I., Kumaravel, T.S., Lohani, A., Pedersen, W.A., Cutler, R.G., Kruman, Y., Haughey, N., Lee, J., Evans, M. & Mattson, M.P. 2002. Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease. Journal of Neuroscience, 22, 1752-1762.
  16. Schaefer, E.J. et al. 2006. Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementia and Alzheimer Disease. Archives of Neurology, 63, 1545-1550.
  17. Freund-Levi;, Y. et al. 2006. w-3 Fatty Acid Treatment in 174 Patients With Mild to Moderate Alzheimer Disease: OmegAD Study: A Randomized Double-blind Trial. Archives of Neurology, 63, 1402-1408.
  18. Quinn, J.F. et al. 2009. A clinical trial of docosahexaenoic acid (DHA) for the treatment of Alzheimer's disease. Presented at the Alzheimer's Association International Conference on Alzheimer's Disease July 11-16 in Vienna.
    Yurko-Mauro, K. et al. 2009. Results of the MIDAS Trial: Effects of Docosahexaenoic Acid on Physiological and Safety Parameters in Age-Related Cognitive Decline. Presented at the Alzheimer's Association International Conference on Alzheimer's Disease July 11-16 in Vienna.
  19. Lim, G.P., Calon, F., Morihara, T., Yang, F., Teter, B., Ubeda, O., Salem, N.Jr, Frautschy, S.A. & Cole, G.M. 2005. A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model. Journal of Neuroscience, 25(12), 3032-3040.
  20. Calon, F. et al. 2004. Docosahexaenoic Acid Protects from Dendritic Pathology in an Alzheimer's Disease Mouse Model. Neuron, 43 (5), 633-645.
  21. Ma, Q-L. et al. 2007. Omega-3 Fatty Acid Docosahexaenoic Acid Increases SorLA/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer's Disease (AD): Relevance to AD Prevention. Journal of Neuroscience, 27 (52), 14299 - 14307.
  22. Collins, M.A. et al. 2008. Alcohol in Moderation, Cardioprotection, and Neuroprotection: Epidemiological Considerations and Mechanistic Studies. Alcoholism: Clinical and Experimental Research, Published Online 20 November.
  23. Truelsen, T., Thudium, D. & Grønbæk, M. 2002. Amount and type of alcohol and risk of dementia: The Copenhagen City Heart Study. Neurology, 59, 1313-1319.
  24. Wang, J. et al. 2008. Grape-Derived Polyphenolics Prevent Aβ Oligomerization and Attenuate Cognitive Deterioration in a Mouse Model of Alzheimer's Disease. Journal of Neuroscience, 28, 6388-6392.
  25. Okello, E.J., Savelev, S.U. & Perry, E.K. 2004. In vitro Anti-beta-secretase and dual anti-cholinesterase activities of Camellia sinensis L. (tea) relevant to treatment of dementia. Phytotherapy Research, 18 (8), 624-627.
  26. Eskelinen, M.H. et al. 2009. Midlife Coffee and Tea Drinking and the Risk of Late-Life Dementia: A Population-based CAIDE Study. Journal of Alzheimer's Disease, 16(1).
  27. Luchsinger, J.A. et al. 2002. Caloric Intake and the Risk of Alzheimer Disease. Archives of Neurology, 59 (8), 1258-1263.
  28. Solomon, A. et al. 2008. Midlife Serum Total Cholesterol and Risk of Alzheimers Disease and Vascular Dementia Three Decades Later. Presented at the American Academy of Neurology Annual Meeting in Chicago, April 16.
  29. Pappolla, M.A. et al. 2003. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology, 61, 199-205.
  30. Yaffe, K., Barrett-Connor, E., Lin, F. & Grady, D. 2002. Serum Lipoprotein Levels, Statin Use, and Cognitive Function in Older Women. Archives of Neurology, 59,378-384.
  31. Kivipelto, M., Helkala, E., Laakso, M. P., Hanninen, T., Hallikainen, M., Alhainen, K., Soininen, H., et al. (2001). Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ, 322(7300), 1447-1451.  http://www.bmj.com/content/322/7300/1447.full
  32. Tan, Z.S., Seshadri, S., Beiser, A., Wilson, P.W.F., Kiel, D.P., Tocco, M., D'Agostino, R.B. & Wolf, P.A. 2003. Plasma Total Cholesterol Level as a Risk Factor for Alzheimer Disease: The Framingham Study. Archives of Internal Medicine, 163, 1053-1057.
  33. Engelhart, M.J., Geerlings, M.I., Ruitenberg, A., van Swieten, J.C., Hofman, A., Witteman, J.C.M. & Breteler, M.M.B. 2002. Diet and risk of dementia: Does fat matter?: The Rotterdam Study. Neurology, 59, 1915-1921.
  34. Kim, W.S. et al. 2007. Role of ABCG1 and ABCA1 in Regulation of Neuronal Cholesterol Efflux to Apolipoprotein E Discs and Suppression of Amyloid-β Peptide Generation. Journal of Biological Chemistry, 282, 2851-2861.
  35. Rönnemaa, E. et al. 2008. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology, first published on April 9 as doi: doi:10.1212/01.wnl.0000310646.32212.3a
  36. Luchsinger, J.A. et al. 2007. Relation of Diabetes to Mild Cognitive Impairment. Archives of Neurology, 64, 570-575.
  37. Yaffe, K. et al. 2006. Glycosylated Hemoglobin Level and Development of Mild Cognitive Impairment or Dementia in Older Women. Journal of Nutrition, Health, and Aging, 10 (4).
  38. Arvanitakis, Z., Wilson, R.S., Bienias, J.L., Evans, D.A. & Bennett, D.A. 2004. Diabetes Mellitus and Risk of Alzheimer Disease and Decline in Cognitive Function. Archives of Neurology, 61, 661-666.
  39. Burdo, J.R. et al. 2008. The pathological interaction between diabetes and presymptomatic Alzheimer's disease. Neurobiology of Aging, Available online 26 March 2008 .
  40. Zhao,W-Q. et al. 2007. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB Journal, published online ahead of print August 24.
  41. Miller, B.C., Eckman, E.A., Sambamurti, K., Dobbs, N., Chow, K.M., Eckman, C.B., Hersh, L.B. & Thiele, D.L. 2003. Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo. PNAS, 100, 6221-6226. published online before print.
  42. Beydoun, M.A., Beydoun, H.A. & Wang, Y. 2008. Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obesity Reviews, 9 (3), 204–218.
  43. Whitmer, R.A., et al. 2008. Central obesity and increased risk of dementia more than three decades later. Neurology, published online ahead of print March 26.
  44. Kivipelto,M. et al. 2006. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurology, advance online publication 3 August
  45. Akterin, S. 2008. From cholesterol to oxidative stress in Alzheimer's disease: A wide perspective on a multifactorial disease. Doctoral thesis, Karolinska Institutet. http://publications.ki.se/xmlui/handle/10616/38590
  46. Erickson, K.I. et al.  2009. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus, Published online 2 January.
  47. Burns, J.M. et al. 2008. Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology, 71, 210-216.
  48. Ravaglia, G. et al. 2007. Physical activity and dementia risk in the elderly. Findings from a prospective Italian study. Neurology, published online ahead of print December 19.
  49. Wang, L., Larson, E.B., Bowen, J.D. & van Belle, G. 2006. Performance-Based Physical Function and Future Dementia in Older People. Archives of Internal Medicine, 166, 1115-1120.
  50. Larson, E.B., Wang, L., Bowen, J.D., McCormick, W.C., Teri, L., Crane, P., & Kukull, W. 2006. Exercise Is Associated with Reduced Risk for Incident Dementia among Persons 65 Years of Age and Older. Annals of Internal Medicine, 144 (2), 73-81.

tags lifestyle: 

Does physical exercise improve cognitive function?

  • A number of studies have provided evidence that physical exercise helps reduce age-related decline in cognitive function, and may prevent or delay dementia.
  • There is some reason to think older (post-menopausal) women may benefit more than older men.
  • While the cognitive benefits of physical exercise for children and younger adults are less clear, there is some evidence that there may be some benefit, although not to the same degree as for older adults.
  • Studies indicate that exercise programs involving both aerobic exercise and strength training are of greatest benefit, with exercise sessions lasting at least 30 minutes.
  • Apart from age and gender, individual differences also play a part in determining how much value exercise is to an individual.

The effects of exercise on cognitive function in older adults

A number of studies in the past few years have provided evidence that physical exercise can ameliorate the effects of aging on the brain, in terms both of preventing or postponing dementia, and reducing the more normal age-related decline in cognitive function. The reasons for the effect are almost certainly multiple, for example:

  • Exercise has clear effects on cardiovascular fitness, and many recent studies have provided converging evidence that there is an association between cardiovascular fitness and mental fitness — "what's good for the heart is good for the brain".
  • Exercise helps control blood sugar levels, and a recent study has found that those with impaired glucose tolerance tend to have a smaller hippocampus.
  • Exercise may increase the flow of oxygen-rich blood to the brain.
  • Exercise may increase self-confidence, and may reduce anxiety and depression.

Interestingly, while exercise benefits both genders, there is some evidence that it may be of greater benefit to women (at older ages). This may be related to estrogen status. There is some evidence that, in females, the benefits of exercise depend on the presence of estrogen. Levels of voluntary physical activity also seem to depend on estrogen status. This may be behind some of the benefit hormone therapy can have on older women's cognitive functioning.

But the undoubted benefits of physical activity for seniors do not imply that exercise has any effect on memory and learning in younger people. That is quite a different question. In seniors, the hope is that exercise will counteract some of the biological wear and tear caused by aging. Does physical fitness matter at younger age levels?

The effects of exercise on cognitive function in children and young adults

Unfortunately, there have been far fewer studies involving young people. However, one study [1] found that, following a 12 week regimen of jogging for 30 minutes two to three times a week, young adults significantly improved their performance on a number of cognitive tests. The scores fell again if participants stopped their running routine.

In this particular case, it does not seem that level of fitness is the primary cause — otherwise, you'd expect test performance not to be so quickly affected by the cessation of physical activity. The researchers suggested that increased oxygen flow to the brain might have been behind the improvement in mental sharpness. Oxygen intake did rise with the joggers' test scores. Supplemental oxygen administration has been found to significantly improve memory formation in healthy young adults, as well as improving reaction time [2].

On the other hand, preliminary results from a series of studies undertaken with elementary school children do indicate a strong relationship between academic achievement and fitness scores. One study found that physically fit children identified visual stimuli faster. Brain activation patterns provided evidence that the fit children allocated more cognitive resources towards the task, as well as processing information faster. [3]

What studies with non-humans tell us

Rodent studies have a big advantage over human studies - many subjects ready to hand, complete control of their environment - and accordingly, it is easier to receive more direct answers. These studies tell us not simply that exercise can be beneficial for learning, but why it might be so.

Studies with mice have made it clear that exercise can:

  • increase levels of BDNF (brain-derived neurotrophic factor; BDNF helps support and strengthen the synapses in the brain (the connections between neurons), as well as helping protect and grow new neurons),
  • stimulate neurogenesis (the creation of new neurons),
  • increase resistance to brain insult, and
  • perhaps promote brain plasticity. [4]

However, while there is no doubt that exercise increases levels of BDNF in the hippocampus, we can’t take it for granted that this is entirely a good thing. Mice bred for 30 generations to be more active (indeed, exercise “addicts”), showed high levels of BDNF and grew more neurons in the hippocampus, and yet performed terribly when attempting to navigate around a maze. Researchers suggested that too much exercise may cause the brain to “max out” in the production of BDNF and neurons, and this may prevent learning. Alternatively, the highly active mice may simply have been too focused on running to concentrate on anything else! [5]

The point is that at the moment, we don’t know for sure what the significance of the exercise-induced increase in BDNF and neurogenesis is. It may be that high levels of exercise place stress on the hippocampus, damaging or killing neurons. The increased levels of BDNF and neuron production may simply be attempts to counteract the damage done. All that's certain is that exercise provokes a lot of activity in the hippocampus, in particular in that particular region of the hippocampus called the dentate gyrus.

Having said that, let's note that this is the first study to demonstrate a case of neurogenesis that is not associated with learning improvement. In general, the production of new neurons is associated with improvement in learning and memory. It would be unwise, therefore, to take these findings as indicating the reverse. What they do suggest is that we cannot assume that such an association always occurs, and that in the case of exercise, it may well be that you can have too much of a good thing! It does seem clear, from this and other studies, that there is a direct association between amount of exercise and BDNF level.

On the subject of whether you can have too much exercise, it's worth noting that a human study found that, while moderate aerobic exercise for up to an hour improved performance on particular cognitive tasks, too much exercise had a deleterious effect. [6]

Brain regions affected by exercise

Notwithstanding the (understandable) emphasis placed on the hippocampus, a critical region for learning and memory, human studies have implicated many parts of the brain. Specifically, one study of seniors found that executive functions were particularly improved by exercise - executive functions are primarily located in the prefrontal cortex. Another study of seniors found reduced grey and white matter in the frontal, temporal, and parietal cortexes of those who were less physically fit. In similar vein, another study of seniors found differences in the middle-frontal and superior parietal regions of the brain as a function of aerobic fitness.

Interestingly, in the possibly first study to look at higher cognitive function during exercise (sustained, moderate), it was found that functions dependent on the prefrontal cortex were impaired, but not those requiring little prefrontal activity. [7]

Exercise and diet

Exercise should not, of course, be considered entirely without reference to diet. The effect of exercise on cardiovascular fitness and blood glucose levels is a counterweight to the effect diet has had in inducing impaired glucose tolerance and cardiovascular problems. A number of rodent studies* have found that a high-fat diet impairs learning and memory. Rodent experiments have also found that exercise can reverse the decrease in BDNF levels in the hippocampus resulting from a high-fat diet, and prevent the deficit in spatial learning induced by such a diet. [8]

The question might therefore arise, if the diet has been healthy, is exercise beneficial? Interestingly, a very recent study involving older beagles found that both a diet enriched with antioxidants and a stimulating environment were helpful in preventing or reducing age-related cognitive decline. That is, each were good, but both was best. This doesn't directly answer the question, of course, but it does seem likely that both diet and exercise are important factors in physical and mental health.

Physical exercise and mental exercise

The beagle study used what is termed an "enriched" environment — typically this involves opportunities for social interaction and mental stimulation, as well as physical activity. A mouse study endeavored to separate the components of such an enriched environment, in order to see whether all were necessary to achieve the observed increased neuron production in the dentate gyrus. Interestingly, they found that voluntary wheel running was in itself sufficient to achieve the level of neurogenesis achieved in typical enrichment conditions. [9]

This is intriguing, but as much as anything else it points to the limitations of rodent studies as models for human behavior. A number of human studies, again, mainly with older adults, point to the value of mental stimulation in protecting against cognitive decline. Interestingly, one such study found ballroom dancing was apparently of (surprising) value in protecting against age-related cognitive decline — it was suggested that there was an intellectual component to it lacking in other physical activities. But perhaps, if I may speculate, we should consider more seriously that activities that combine intellectual and physical (and perhaps social) attributes might be best of all.

It does seem clear that, while both mental stimulation and physical exercise might both help cognitive function, they do so in quite different ways, for different reasons.

Recommendations

An analysis of 18 studies [10] on the effects of exercise on cognitive function in older adults concluded that:

  • exercise programs involving both aerobic exercise and strength training produced better results on cognitive abilities than either one alone
  • more than 30 minutes of exercise per session produce the greatest benefit

Caveat: Not everyone benefits equally from exercise

It does seem clear that older adults benefit more from exercise than younger people, as far as cognitive function is concerned. It also seems that older women, especially those on hormone-replacement therapy, receive greater cognitive benefits from exercise than men.

Generalisations aside, it is as well to remember the findings of a very recent study showing that, while most people benefit (physically) from exercise, the degree of benefit is hugely variable between individuals, and some people don’t benefit at all! [11]

* In one study, young adult male mice were divided into four groups by diet: normal (control) diet, high-saturated-fat diet, high-sugar diet, and diet high in saturated fats and sugar. They were kept on the diet for four months, during which mice on the high-fat and high-fat-&-sugar diets gained significantly more weight than those on the control and high sugar diets. At the end of that time, the mice were tested on a maze task. Mice on the high-fat and high-fat-&-sugar diets performed worse than the other mice. The mice were then exposed to a neurotoxin called kainic acid, which is known to damage nerve cells in the hippocampus. Mice on the high-fat and high-fat-&-sugar diets were significantly more impaired by the neurotoxin.
In another mouse study, obese mice were fed a diet containing about 10% fat for seven months, while control mice were fed standard lab chow containing only 5% fat. On testing, it was found that the obese mice took significantly more trials than the normal-weight mice to both acquire and retain a memory of a foot shock. They also required significantly more trials than control mice to learn to press a lever for milk reinforcement.
A rat study explored whether a diet high in cholesterol and hydrogenated fats affected working memory in middle-aged rats (corresponding to 60 and older for humans). The high-fat, high-cholesterol diet produced significantly higher plasma triglycerides, total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol compared with controls. Weight increase and food consumption were similar between the groups. Animals on the high-fat regimen made more errors than animals fed the control diet, especially during the trial that placed the highest demand on their working memory.
Another rat study found that a diet high in fats and carbohydrates worsened cognitive deficits in rats exposed to repeated brief periods of low oxygen during sleep (as experienced by people with sleep apnea). Press release

See news reports

References: 

  1. Harada, T., Okagawa, S., & Kubota, K. (2004). Jogging improved performance of a behavioral branching task: implications for prefrontal activation. Neuroscience Research, 49(3), 325–337.
  2. Scholey, A.B., Moss, M.C., Neave, N. & Wesnes, K. 1999. Cognitive Performance, Hyperoxia, and Heart Rate Following Oxygen Administration in Healthy Young Adults. Physiology & Behavior, 67 (5), 783-789.
  3. Hillman, C. & Buck, S. 2004. Physical Fitness and Cognitive Function in Healthy Preadolescent Children. Presented at the annual meeting of the Society for Psychophysiological Research in Santa Fe, N.M., Oct. 20-24. Press release
  4. Cotman, C.W. & Berchtold, N.C. 2002. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends in Neurosciences, 25 (6), 295-301.
  5. Rhodes, J.S., van Praag, H., Jeffrey, S., Girard, I., Mitchell, G.S., Garland, T.Jr. & Gage, F.H. 2003. Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. Behavioral Neuroscience, 117(5), 1006-1016.
  6. Tomporowski,P.D. 2003. Effects of acute bouts of exercise on cognition. Acta Psychol (Amst), 112, 297-324.
  7. Dietrich, A. & Sparling, P.B. 2004. Endurance exercise selectively impairs prefrontal-dependent cognition. Brain and Cognition, 55 (3), 516-524.
  8. Molteni, R., Wu, A., Vaynman, S., Ying, Z., Barnard, R.J. & Gómez-Pinilla, F. 2004. Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor. Neuroscience, 123 (2), 429-440.
  9. van Praag, H., Kempermann, G. & Gage, F.H. 1999. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nature Neuroscience, 2 (3), 266-70.
  10. Colcombe, S. & Kramer, A.F. 2003. Fitness effects on the cognitive function of older adults: A meta-analytic study. Psychological Science, 14, 125-130.
  11. Bouchard, C. 2004. Reported at the Australian Health and Medical Research Congress in Sydney, Australia. http://www.newscientist.com/article/dn6735-some-people-are-immune-to-exe...

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