Alzheimers prevention

Rapamycin makes young mice learn better and prevents decline in old mice

July, 2012

Further evidence from mice studies that the Easter Island drug improves cognition, in young mice as well as old.

I have reported previously on research suggesting that rapamycin, a bacterial product first isolated from soil on Easter Island and used to help transplant patients prevent organ rejection, might improve learning and memory. Following on from this research, a new mouse study has extended these findings by adding rapamycin to the diet of healthy mice throughout their life span. Excitingly, it found that cognition was improved in young mice, and abolished normal cognitive decline in older mice.

Anxiety and depressive-like behavior was also reduced, and the mice’s behavior demonstrated that rapamycin was acting like an antidepressant. This effect was found across all ages.

Three "feel-good" neurotransmitters — serotonin, dopamine and norepinephrine — all showed significantly higher levels in the midbrain (but not in the hippocampus). As these neurotransmitters are involved in learning and memory as well as mood, it is suggested that this might be a factor in the improved cognition.

Other recent studies have suggested that rapamycin inhibits a pathway in the brain that interferes with memory formation and facilitates aging.

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Coffee helps prevent progression to dementia

July, 2012

A 4-year study of older adults has found that low levels of caffeine were linked to MCI progressing to dementia, apparently by mediating lower levels of anti-inflammatory proteins.

Following on from mouse studies, a human study has investigated whether caffeine can help prevent older adults with mild cognitive impairment from progressing to dementia.

The study involved 124 older adults (65-88) who were thoroughly cognitively assessed, given brain scans, and had a fasting blood sample taken. They were then followed for 2 to 4 years, during which their cognitive status was re-assessed annually. Of the 124 participants, 69 (56%) were initially assessed as cognitively normal (average age 73), 32 (26%) with MCI (average age 76.5), and 23 (19%) with dementia (average age 77). The age differences were significant.

Those with MCI on initial assessment showed significantly lower levels of caffeine in their blood than those cognitively healthy; levels in those with dementia were also lower but not significantly. Those initially healthy who developed MCI over the study period similarly showed lower caffeine levels than those who didn’t develop MCI, but again, due to the wide individual variability (and the relatively small sample size), this wasn’t significant. However, among those with MCI who progressed to dementia (11, i.e. a third of those with MCI), caffeine levels were so much lower that the results were significant.

This finding revealed an apparently critical level of caffeine dividing those who progressed to dementia and those who did not — more specifically, all of those who progressed to dementia were below this level, while around half of those who remained stable were at the level or above. In other words, low caffeine would seem to be necessary but not sufficient.

On the other hand (just to show that this association is not as simple as it appears), those already with dementia had higher caffeine levels than those with MCI who progressed to dementia.

The critical factor may have to do with three specific cytokines — GCSF, IL-10, and IL-6 — which all showed markedly lower levels in those converting from MCI to dementia. Comparison of the three stable-MCI individuals with the highest caffeine levels and the three with the lowest levels, and the three from the MCI-to-dementia group with comparable low levels, revealed that high levels of those cytokines were matched with high caffeine levels, while, in both groups, low caffeine levels were matched to low levels of those cytokines.

These cytokines are associated with inflammation — an established factor in cognitive decline and dementia.

The level of coffee needed to achieve the ‘magic’ caffeine level is estimated at around 3 cups a day. While caffeine can be found in other sources, it is thought that in this study, as in the mouse studies, coffee is the main source. Moreover, mouse research suggests that caffeine is interacting with an as yet unidentified component of coffee to boost levels of these cytokines.

This research has indicated that caffeine has several beneficial effects on the brain, including suppressing levels of enzymes that produce amyloid-beta, as well as these anti-inflammatory effects.

It’s suggested that the reason high levels of caffeine don’t appear to benefit those with dementia is because higher levels of these cytokines have become re-established, but this immune response would appear to come too late to protect the brain. This is consistent with other evidence of the importance of timing.

Do note that in mouse studies, the same benefits were not associated with decaffeinated coffee.

While this study has some limitations, the findings are consistent with previous epidemiologic studies indicating coffee/caffeine helps protect against cognitive impairment and dementia. Additionally, in keeping with the apparent anti-inflammatory action, a long-term study tracking the health and coffee consumption of more than 400,000 older adults recently found that coffee drinkers had reduced risk of dying from heart disease, lung disease, pneumonia, stroke, diabetes, infections, injuries and accidents.

Reference: 

Cao, C., Loewenstein, D. a, Lin, X., Zhang, C., Wang, L., Duara, R., Wu, Y., et al. (2012). High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia. Journal of Alzheimer’s disease : JAD, 30(3), 559–72. doi:10.3233/JAD-2012-111781

Freedman, N.D. et al. 2012. Association of Coffee Drinking with Total and Cause-Specific Mortality. N Engl J Med, 366, 1891-1904.

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Omega-3 oil linked to lower level of Alzheimer's protein

June, 2012

A new study adds to growing evidence that higher levels of omega-3 fatty acids help protect against Alzheimer’s disease.

A new study, involving 1,219 dementia-free older adults (65+), has found that the more omega-3 fatty acids the person consumed, the lower the level of beta-amyloid in the blood (a proxy for brain levels). Consuming a gram of omega-3 more than the average per day was associated with 20-30% lower beta-amyloid levels. A gram of omega-3 equates to around half a fillet of salmon per week.

Participants provided information about their diet for an average of 1.2 years before their blood was tested for beta-amyloid. Other nutrients investigated —saturated fatty acids, omega-6 polyunsaturated fatty acids, mono-unsaturated fatty acid, vitamin E, vitamin C, beta-carotene, vitamin B12, folate and vitamin D — were not associated with beta-amyloid levels.

The results remained after adjusting for age, education, gender, ethnicity, amount of calories consumed and APOE gene status.

The findings are consistent with previous research associating higher levels of omega-3 and/or fish intake with lower risk of Alzheimer’s. Additionally, another recent study provides evidence that the brains of those with Alzheimer’s disease, MCI, and the cognitively normal, all have significantly different levels of omega-3 and omega-6 fatty acids. That study concluded that the differences were due to both consumption and metabolic differences.

Reference: 

[2959] Gu, Y., Schupf N., Cosentino S. A., Luchsinger J. a, & Scarmeas N.
(2012).  Nutrient Intake and Plasma Β-Amyloid.
Neurology. 78(23), 1832 - 1840.

Cunnane, S.C. et al. 2012. Plasma and Brain Fatty Acid Profiles in Mild Cognitive Impairment and Alzheimer’s Disease. Journal of Alzheimer’s Disease, 29 (3), 691-697.

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Type of fat, not amount of fat, linked to cognitive decline in old age

June, 2012

A large four-year study of older women has found high amounts of saturated fat were associated with greater cognitive decline, while higher amounts of monounsaturated fat were associated with better performance.

Data from the Women's Health Study, involving 6,183 older women (65+), has found that it isn’t the amount of fat but the type of fat that is associated with cognitive decline. The women were given three cognitive function tests at two-yearly intervals, and filled out very detailed food frequency surveys at the beginning of the study.

Women who consumed the highest amounts of saturated fat (such as that from animals) had significantly poorer cognitive function compared to those who consumed the lowest amounts. Women who instead had a high intake of monounsaturated fats (such as olive oil) had better cognitive scores over time. Total fat, polyunsaturated fat, and trans fat, were not associated with cognitive performance.

The findings are consistent with research associating the Mediterranean diet (high in olive oil) with lower Alzheimer’s risk, and studies linking diets high in saturated fats with greater cognitive decline.

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Resistance training benefits seniors with MCI

May, 2012

Six months of resistance training has improved executive function and associative memory in older women with mild cognitive impairment.

A study involving 86 older women (aged 70-80) with probable MCI has compared the effectiveness of resistance and aerobic training in improving executive function. The women were randomly allocated either to resistance training, aerobic training, or balance and tone training (control group). The programs all ran twice weekly for six months.

The 60-minute classes involved lifting weights (resistance training), outdoor walking (aerobic training), or stretching, balancing, and relaxation exercises (control).

Executive function was primarily assessed by the Stroop Test (measuring selective attention/conflict resolution), and also by Trail Making Tests (set-shifting) and Verbal Digits Tests (working memory). Associative memory (face-scene pairs) and problem-solving ability (Everyday Problems Test) were also assessed.

The study found that resistance training significantly improved performance on the Stroop Test and also the associative memory task. These improvements were associated with changes in some brain regions. In contrast to previous studies in healthy older adults, aerobic training didn’t produce any significant cognitive improvement, although it did produce significantly better balance and mobility, and cardiovascular capacity, compared to the control.

Interestingly, a previous study from these researchers demonstrated that it took a year of resistance training to achieve such results in cognitively healthy women aged 65-75. This suggests that the benefits may be greater for those at greater risk.

It may be that the greater benefits of resistance training over aerobic training are not be solely due to physical differences in the exercise. The researchers point out that resistance training required more cognitive engagement (“If you’re lifting weights you have to monitor your sets, your reps, you use weight machines and you have to adjust the seat, etc.”) compared to walking.

Note that impaired associative memory is one of the earliest cognitive functions affected in Alzheimer’s.

It’s also worth noting that exercise compliance was low (55-60%), suggesting that benefits might have been greater if the participants had been more motivated — or found the programs more enjoyable! The failure of aerobic exercise to improve cognition is somewhat surprising, and perhaps it, too, may be attributed to insufficient engagement — in terms of intensity as well as amount.

The researchers have put up a YouTube video of the resistance training exercises used in the study.

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Being active reduces Alzheimer's risk

May, 2012
  • A large study provides evidence that higher levels of everyday activity help prevent Alzheimer’s, although more intense activity is even better.

A four-year study involving 716 elderly (average age 82) has revealed that those who were most physically active were significantly less likely to develop Alzheimer’s than those least active. The study is unique in that, in addition to self-reports of physical and social activity, activity was objectively measured (for up to 10 days) through a device worn on the wrist. This device (an actigraph) enabled everyday activity, such as cooking, washing the dishes, playing cards and even moving a wheelchair with a person's arms, to be included in the analysis.

Cognitive performance was assessed annually. Over the study period, 71 participants (10%) developed Alzheimer’s.

The study found that those in the bottom 10% of daily physical activity were more than twice as likely (2.3 times) to develop Alzheimer's disease as those in the top 10%. Those in the bottom 10% of intensity of physical activity were almost three times (2.8 times) as likely to develop Alzheimer's disease as people in the top 10%.

Moreover, the level of activity was associated with the rate of cognitive decline.

The association remained after motor function, depression, chronic health conditions, and APOE gene status were taken into account.

The findings should encourage anyone who feels that physical exercise is beyond them to nevertheless engage in milder forms of daily activity.

 

Addendum:

Another recent study, involving 331 cognitively healthy elderly, has also found that higher levels of physical activity were associated with better cognitive performance (specifically, a shorter time to complete the Trail-making test, and higher levels of verbal fluency) and less brain atrophy. Activity levels were based on the number of self-reported light and hard activities for at least 30 minutes per week. Participants were assessed in terms of MMSE score, verbal fluency, and visuospatial ability.

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Low levels of omega-3 fatty acids linked to brain aging

April, 2012
  • A large study has found that older adults with low levels of omega-3 fatty acids had greater brain atrophy and more white matter damage.

A study involving 1,575 older adults (aged 58-76) has found that those with DHA levels in the bottom 25% had smaller brain volume (equivalent to about 2 years of aging) and greater amounts of white matter lesions. Those with levels of all omega-3 fatty acids in the bottom quarter also scored lower on tests of visual memory, executive function, and abstract thinking.

The finding adds to the evidence that higher levels of omega-3 fatty acids reduce dementia risk.

For more about omega-3 oils and cognition

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Walking speed and grip strength may predict dementia, stroke risk

March, 2012

More evidence comes for a link between lower physical fitness and increased risk of dementia in a large study that extends earlier findings to middle-aged and younger-old.

Following on from research showing an association between lower walking speed and increased risk of dementia, and weaker hand grip strength and increased dementia risk, a large study has explored whether this association extends to middle-aged and younger-old adults.

Part of the long-running Framingham study, the study involved 2,410 men and women with an average age of 62, who underwent brain scans and tests for walking speed, hand grip strength and cognitive function. During the follow-up period of up to 11 years, 34 people (1.4%) developed dementia (28 Alzheimer’s) and 79 people (3.3%) had a stroke.

Those who had a slower walking speed at the start of the study were one-and-a-half times more likely to develop dementia compared to people with faster walking speed, while stronger hand grip strength was associated with a 42% lower risk of stroke or transient ischemic attack in people over age 65.

Slower walking speed and weaker hand grip strength were also associated with lower brain volume and poorer cognitive performance. Specifically, those with slower walking speed scored significantly worse on tests of visual reproduction, paired associate learning, executive function, visual organization, and language (Boston Naming test). Higher hand grip strength was associated with higher scores on tests of visual reproduction, executive function, visual organization, language and abstraction (similarities test).

While the nature of the association is not yet understood, the findings do seem to support the benefits of physical fitness. At the least, these physical attributes can serve as pointers to the need for more investigation of an older person’s brain health. But they might also serve as a warning to improve physical fitness.

Reference: 

Camargo, E.C., Beiser, A., Tan, Z.S., Au, R., DeCarli, C., Pikula, A., Kelly-Hayes, M., Kase, C., Wolf, P. & Seshadri, S. 2012. Walking Speed, Handgrip Strength and Risk of Dementia and Stroke: The Framingham Offspring Study. To be presented April 25 at the American Academy of Neurology's 64th Annual Meeting in New Orleans.

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'Exergames' may provide greater cognitive benefit for older adults

February, 2012

An intriguing pilot study finds that regular exercise on a stationary bike enhanced with a computer game-type environment improves executive function in older adults more than ordinary exercise on a stationary bike.

We know that physical exercise greatly helps you prevent cognitive decline with aging. We know that mental stimulation also helps you prevent age-related cognitive decline. So it was only a matter of time before someone came up with a way of combining the two. A new study found that older adults improved executive function more by participating in virtual reality-enhanced exercise ("exergames") that combine physical exercise with computer-simulated environments and interactive videogame features, compared to the same exercise without the enhancements.

The Cybercycle Study involved 79 older adults (aged 58-99) from independent living facilities with indoor access to a stationary exercise bike. Of the 79, 63 participants completed the three-month study, meaning that they achieved at least 25 rides during the three months.

Unfortunately, randomization was not as good as it should have been — although the researchers planned to randomize on an individual basis, various technical problems led them to randomize on a site basis (there were eight sites), with the result that the cybercycle group and the control bike group were significantly different in age and education. Although the researchers took this into account in the analysis, that is not the same as having groups that match in these all-important variables. However, at least the variables went in opposite directions: while the cybercycle group was significantly younger (average 75.7 vs 81.6 years), it was significantly less educated (average 12.6 vs 14.8 years).

Perhaps also partly off-setting the age advantage, the cybercycle group was in poorer shape than the control group (higher BMI, glucose levels, lower physical activity level, etc), although these differences weren’t statistically significant. IQ was also lower for the cybercycle group, if not significantly so (but note the high averages for both groups: 117.6 vs 120.6). One of the three tests of executive function, Color Trails, also showed a marked group difference, but the large variability in scores meant that this difference was not statistically significant.

Although participants were screened for disorders such as Alzheimer’s and Parkinson’s, and functional disability, many of both groups were assessed as having MCI — 16 of the 38 in the cybercycle group and 14 of the 41 in the control bike group.

Participants were given cognitive tests at enrolment, one month later (before the intervention began), and after the intervention ended. The stationary bikes were identical for both groups, except the experimental bike was equipped with a virtual reality display. Cybercycle participants experienced 3D tours and raced against a "ghost rider," an avatar based on their last best ride.

The hypothesis was that cybercycling would particularly benefit executive function, and this was borne out. Executive function (measured by the Color Trails, Stroop test, and Digits Backward) improved significantly more in the cybercycle condition, and indeed was the only cognitive task to do so (other cognitive tests included verbal fluency, verbal memory, visuospatial skill, motor function). Indeed, the control group, despite getting the same amount of exercise, got worse at the Digits Backward test, and failed to show any improvement on the Stroop test.

Moreover, significantly fewer cybercyclists progressed to MCI compared to the control group (three vs nine).

There were no differences in exercise quantity or quality between the two groups — which does argue against the idea that cyber-enhanced physical activity would be more motivating. However, the cybercycling group did tend to comment on their enjoyment of the exercise. While the enjoyment may not have translated into increased activity in this situation, it may well do so in a longer, less directed intervention — i.e. real life.

It should also be remembered that the intervention was relatively short, and that other cognitive tasks might take longer to show improvement than the more sensitive executive function. This is supported by the fact that levels of the brain growth factor BDNF, assessed in 30 participants, showed a significantly greater increase of BDNF in cybercyclists.

I should also emphasize that the level of physical exercise really wasn't that great, but nevertheless the size of the cybercycle's effect on executive function was greater than usually produced by aerobic exercise (a medium effect rather than a small one).

The idea that activities that combine physical and mental exercise are of greater cognitive benefit than the sum of benefits from each type of exercise on its own is not inconsistent with previous research, and in keeping with evidence from animal studies that physical exercise and mental stimulation help the brain via different mechanisms. Moreover, I have an idea that enjoyment (in itself, not as a proxy for motivation) may be a factor in the cognitive benefits derived from activities, whether physical or mental. Mere speculation, derived from two quite separate areas of research: the idea of “flow” / “being in the zone”, and the idea that humor has physiological benefits.

Of course, as discussed, this study has a number of methodological issues that limit its findings, but hopefully it will be the beginning of an interesting line of research.  

Reference: 

[2724] Anderson-Hanley, C., Arciero P. J., Brickman A. M., Nimon J. P., Okuma N., Westen S. C., et al.
(2012).  Exergaming and Older Adult Cognition.
American Journal of Preventive Medicine. 42(2), 109 - 119.

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Diet linked to brain atrophy in old age

January, 2012
  • A more rigorous measurement of diet finds that dietary factors account for nearly as much brain shrinkage as age, education, APOE genotype, depression and high blood pressure combined.

The study involved 104 healthy older adults (average age 87) participating in the Oregon Brain Aging Study. Analysis of the nutrient biomarkers in their blood revealed that those with diets high in omega 3 fatty acids and in vitamins C, D, E and the B vitamins had higher scores on cognitive tests than people with diets low in those nutrients, while those with diets high in trans fats were more likely to score more poorly on cognitive tests.

These were dose-dependent, with each standard deviation increase in the vitamin BCDE score ssociated with a 0.28 SD increase in global cognitive score, and each SD increase in the trans fat score associated with a 0.30 SD decrease in global cognitive score.

Trans fats are primarily found in packaged, fast, fried and frozen food, baked goods and margarine spreads.

Brain scans of 42 of the participants found that those with diets high in vitamins BCDE and omega 3 fatty acids were also less likely to have the brain shrinkage associated with Alzheimer's, while those with high trans fats were more likely to show such brain atrophy.

Those with higher omega-3 scores also had fewer white matter hyperintensities. However, this association became weaker once depression and hypertension were taken into account.

Overall, the participants had good nutritional status, but 7% were deficient in vitamin B12 (I’m surprised it’s so low, but bear in mind that these are already a select group, being healthy at such an advanced age) and 25% were deficient in vitamin D.

The nutrient biomarkers accounted for 17% of the variation in cognitive performance, while age, education, APOE genotype (presence or absence of the ‘Alzheimer’s gene’), depression and high blood pressure together accounted for 46%. Diet was more important for brain atrophy: here, the nutrient biomarkers accounted for 37% of the variation, while the other factors accounted for 40% (meaning that diet was nearly as important as all these other factors combined!).

The findings add to the growing evidence that diet has a significant role in determining whether or not, and when, you develop Alzheimer’s disease.

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