inflammation alzheimers

Gene variant makes some brains more resilient to Alzheimer's

Analysis of 700 subjects from the Alzheimer's Disease Neuroimaging Initiative has revealed a genetic mutation (rs4728029) that’s associated with people who develop Alzheimer’s pathology but don’t show clinical symptoms in their lifetime. The gene appears to be related to an inflammatory response in the presence of phosphorylated tau. In other words, some people’s brains react to phosphorylated tau with a ‘bad’ inflammatory response, while others don’t.

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Blocking inflammation receptor helps Alzheimer's mice

Blocking a receptor involved in inflammation in the brains of mice with severe Alzheimer’s produced marked recovery in blood flow and vascular reactivity, a dramatic reduction in toxic amyloid-beta, and significant improvements in learning and memory.

The receptor was the bradykinin B1 receptor (B1R), and the finding confirms a role of B1R, and neuroinflammation, in the development of Alzheimer’s. It also points to a new target for therapy.

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Impaired recovery from inflammation linked to Alzheimer's

Analyses of cerebrospinal fluid from 15 patients with Alzheimer's disease, 20 patients with mild cognitive impairment, and 21 control subjects, plus brain tissue from some of them, has found that those with Alzheimer’s had lower levels of a particular molecule involved in resolving inflammation. These ‘specialized pro-resolving mediators’ regulate the tidying up of the damage done by inflammation and the release of growth factors that stimulate tissue repair.

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How inflammation and hypoxia damage the brain

A new study shows that a combination of inflammation and hypoxia activates microglia in a way that persistently weakens the connection between neurons, contributing to brain damage in conditions such as stroke and Alzheimer's disease.

http://www.eurekalert.org/pub_releases/2014-03/uobc-scb031214.php

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Caffeine may block inflammation linked to cognitive impairment

November, 2012

A mouse study indicates that caffeine can help prevent inflammation occurring in the brain, by blocking an early response to cell damage.

Caffeine has been associated with a lower of developing Alzheimer's disease in some recent studies. A recent human study suggested that the reason lies in its effect on proteins involved in inflammation. A new mouse study provides more support for this idea.

In the study, two groups of mice, one of which had been given caffeine, were exposed to hypoxia, simulating what happens in the brain during an interruption of breathing or blood flow. When re-oxygenated, caffeine-treated mice recovered their ability to form a new memory 33% faster than the other mice, and the caffeine was observed to have the same anti-inflammatory effect as blocking interleukin-1 (IL-1) signaling.

Inflammation is a key player in cognitive impairment, and IL-1 has been shown to play a critical role in the inflammation associated with many neurodegenerative diseases.

It was found that the hypoxic episode triggered the release of adenosine, the main component of ATP (your neurons’ fuel). Adenosine is released when a cell is damaged, and this leakage into the environment outside the cell begins a cascade that leads to inflammation (the adenosine activates an enzyme, caspase-1, which triggers production of the cytokine IL-1β).

But caffeine blocks adenosine receptors, stopping the cascade before it starts.

The finding gives support to the idea that caffeine may help prevent cognitive decline and impairment.

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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.

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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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