Latest Research News
A two-year study which involved metabolic testing of 50 people, suggests that Alzheimer's disease consists of three distinct subtypes, each one of which may need to be treated differently. The finding may help explain why it has been so hard to find effective treatments for the disease.
The subtypes are:
- Inflammatory, in which markers such as C-reactive protein and serum albumin to globulin ratios are increased.
- Non-inflammatory, in which these markers are not increased but other metabolic abnormalities (such as insulin resistance, hypovitaminosis D, and hyper-homocysteinemia) are present. This tends to affect slightly older individuals than the first subtype: 80s rather than 70s.
- Cortical, which affects relatively young individuals (typically 50s- early 70s) and appears more widely distributed across the brain than the other subtypes, showing widespread cortical atrophy rather than marked hippocampal atrophy. It typically presents with language and number difficulties first, rather than memory loss. Typically, there is an impaired ability to hold onto a train of thought. It is often misdiagnosed, typically affects people without a family history of Alzheimer's, who do not have an Alzheimer's-related gene, and is associated with a significant zinc deficiency (Zinc is implicated in multiple Alzheimer's-related metabolic processes, such as insulin resistance, chronic inflammation, ADAM10 proteolytic activity, and hormonal signaling. Zinc deficiency is relatively common, and associated with increasing age.).
The cortical subtype appears to be fundamentally a different condition than the other two.
I note a study I reported on last year, that found different molecular structures of amyloid-beta fibrils in the brains of Alzheimer's patients with different clinical histories and degrees of brain damage. That was a very small study, indicative only. However, I do wonder if there's any connection between these two findings. At the least, I think this approach a promising one.
The idea that there are different types of Alzheimer's disease is of course consistent with the research showing a variety of genetic risk factors, and an earlier study indicating at least two pathways to Alzheimer's.
It's also worth noting that the present study built on an earlier study, which showed that a program of lifestyle, exercise and diet changes designed to improve the body's metabolism reversed cognitive decline within 3-6 months in nine out of 10 patients with early Alzheimer's disease or its precursors. Note that this was a very small pilot program, and needs a proper clinical trial. Nevertheless, it is certainly very interesting.
Bredesen, D.E. 2015. Metabolic profiling distinguishes three subtypes of Alzheimer's disease. AGING, 7 (8), 595-600. Full text at http://www.impactaging.com/papers/v7/n8/full/100801.html
Bredesen, D.E. 2014. Reversal of cognitive decline: A novel therapeutic program. AGING, Vol 6, No 9 , pp 707-717. Full text at http://www.impactaging.com/papers/v6/n9/full/100690.html
A post-mortem study of five Alzheimer's and five control brains has revealed the presence of iron-containing microglia in the subiculum of the Alzheimer's brains only. The subiculum lies within the hippocampus, a vital memory region affected early in Alzheimer's. None of the brains of those not diagnosed with Alzheimer's had the iron deposits or the microglia, in that brain region, while four of the five Alzheimer's brains contained the iron-containing microglia.
The microglia were mostly in an inflamed state. Growing evidence implicates brain inflammation in the development of Alzheimer's.
There was no consistent association between iron-laden microglia and amyloid plaques or tau in the same area.
Obviously, this is only a small study, and more research needs to be done to confirm the finding. However, this is consistent with previous findings of higher levels of iron in the hippocampi of Alzheimer's brain.
At the moment, we don't know how the iron gets into brain tissue, or why it accumulates in the subiculum. However, the researchers speculate that it may have something to do with micro-injury to small cerebral blood vessels.
This is an interesting finding that may lead to new treatment or prevention approaches if confirmed in further research.
(Submitted). Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease.
Neurobiology of Aging.
A comparison of Alzheimer’s prevalence across the world using 'age-standardized' data (which predict Alzheimer's rates if all countries had the same population birth rate, life expectancy and age structure) has found a strong correlation between national sanitation levels and Alzheimer's, with better hygiene associated with higher rates of Alzheimer’s.
This fits in with the idea that’s been floating around for a while, that over-sanitized environments reduce exposure to a diverse range of microorganisms, perhaps impairing proper development of the immune system. Hence, the rising incidence of allergies and auto-immune diseases in developed countries.
The study compared data from 192 countries. Higher rates of Alzheimer's were seen in countries with higher levels of sanitation, countries with much lower rates of infectious disease, and more urbanized countries. For example, UK and France have 9% higher Alzheimer's rates than Kenya and Cambodia; Switzerland and Iceland have 12% higher rates of Alzheimer's than China and Ghana; UK and Australia have 10% higher rates than Bangladesh and Nepal.
Differences in levels of sanitation, infectious disease and urbanization accounted respectively for 33%, 36% and 28% of the discrepancy in Alzheimer's rates between countries.
Previous research has shown that in the developed world, dementia rates doubled every 5.8 years compared with 6.7 years in low income, developing countries, and that Alzheimer's prevalence in Latin America, China and India are all lower than in Europe, and, within those regions, lower in rural compared with urban settings.
Having said all that, I would query the reliability of Alzheimer’s statistics from less developed countries. A recent study from China, for example, found dramatic under-reporting of Alzheimer’s. While this is certainly a plausible hypothesis, I think the wide variability in diagnosing Alzheimer’s stands in the way of this sort of comparison.
Full text freely available at http://emph.oxfordjournals.org/content/2013/1/173.full
(2013). Hygiene and the world distribution of Alzheimer’s disease Epidemiological evidence for a relationship between microbial environment and age-adjusted disease burden.
Evolution, Medicine, and Public Health. 2013(1), 173 - 186.
Analysis of post-mortem with and without dementia has found lipopolysaccharide, a component of an oral bacterium (Porphyromonas gingivalis), in four out of 10 Alzheimer’s disease brain samples, but not in any of the 10 brains of people who didn’t have Alzheimer’s.
Gingivitis is extremely common, and about 64% of American seniors (65+) have moderate or severe periodontal disease.
The finding adds to evidence linking gum disease and Alzheimer’s.
(2013). Determining the Presence of Periodontopathic Virulence Factors in Short-Term Postmortem Alzheimer's Disease Brain Tissue.
Journal of Alzheimer's Disease. 36(4), 665 - 677.
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.
(2014). Genetic modification of the relationship between phosphorylated tau and neurodegeneration.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association.
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.
(2013). Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer’s disease mice.
Journal of Neuroinflammation. 10(1),
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. Lower levels of these molecules also correlated with a lower degree of cognitive function.
The pro-resolving molecules identified so far are derivatives of omega-3 fatty acids, providing support for the idea that dietary supplements of these may provide benefit.
(2014). Resolution of inflammation is altered in Alzheimer's disease.
Alzheimer's & Dementia.
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.
(2014). Microglial CR3 Activation Triggers Long-Term Synaptic Depression in the Hippocampus via NADPH Oxidase.
Neuron. 82(1), 195 - 207.
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.
(2012). Hypoxia/Reoxygenation Impairs Memory Formation via Adenosine-Dependent Activation of Caspase 1.
The Journal of Neuroscience. 32(40), 13945 - 13955.
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.
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.
Older news items (pre-2010) brought over from the old website
Evidence challenges inflammation theory for Alzheimer's
Although it has long been theorized that inflammation plays a role in the development of Alzheimer’s, repeated studies have failed to find consistent evidence that anti-inflammatory drugs are helpful. Now a brain tissue study reveals that supporting brain cells called microglia are not activated in the presence of tau tangles in the brains of Alzheimer’s patients, as has been predicted, and as would be the case if there were inflammation. Instead, microglia are degenerating. It’s suggested that it is this loss of microglia that contributes to the loss of neurons, and thus to the development of dementia. The next step is to find out why the microglia are dying.
Streit, W.J. et al. 2009. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathologica, Published online ahead of print.
Blood inflammation plays role in Alzheimer's disease
Data from the Framingham Heart Study has found that those with the highest amount of cytokines (protein messengers that trigger inflammation) in their blood were more than twice as likely to develop Alzheimer's disease as those with the lowest amount of cytokines, providing further evidence that inflammation plays a role in the development of Alzheimer's disease.
Tan, Z.S. et al. 2007. Inflammatory markers and the risk of Alzheimer disease: The Framingham Study. Neurology, 68, 1902-1908.
Alzheimer's disease linked to early inflammation
A new study of dementia in identical twins suggests that exposure to inflammation early in life quadruples one's risk of developing Alzheimer's disease. The study involved sifting the 20,000 participants in the Swedish Twin Registry for the 109 "discordant" pairs where only one twin had been diagnosed with dementia. Answers to health questions in the survey enabled the researchers to build a crude indicator of periodontal disease, measured indirectly by teeth lost or loose. Because this is not a direct measure of inflammation, the results need to be confirmed, but they do suggest that an inflammatory burden early in life, as represented by chronic gum disease, may have severe consequences later. The study also found that mental activities at age 40 did not seem to lower the risk of developing Alzheimer's, and the level of education was not a large factor once genes were taken into account (nevertheless, those with less high school and college education had 1.6 times the risk of dementia). Previous studies have shown that Alzheimer's is strongly genetic: If one twin has the disease, his or her identical twin has a 60% chance of developing it.
The study was presented at the first Alzheimer's Association International Conference on Prevention of Dementia, to be held June 18-21 in Washington, D.C.
Antibody detection in Alzheimer's may improve diagnosis, treatment
A study has found that people with Alzheimer’s disease have three to four times more antibodies to RAGE (receptor for advanced glycation end products) and beta amyloid — both major players in Alzheimer’s — than their healthy counterparts. The ability to measure these specific antibody levels could lead to a method for very early diagnosis. The finding may also point to a new treatment approach. The study supports the theory that autoimmunity and resulting inflammation play a big role in Alzheimer’s.
Mruthinti, S., Buccafusco, J.J., Hill, W.D., Waller, J.L., Jackson, T.W., Zamrini, E.Y. & Schade, R.F. 2004. Autoimmunity in Alzheimer’s disease: increased levels of circulating IgGs binding Ab and RAGE peptides. Neurobiology of Aging, 25 (8), 1023-1032.
A new hypothesis about Alzheimer's
A new theory about the cause of Alzheimer's disease has been proposed. According to this theory, Alzheimer’s arises as a consequence of inflammation, which creates abnormal metabolites out of normal brain molecules. These abnormal metabolites then modify "amyloid beta" proteins in the brain and cause them to misfold, thus accumulating into the fibrils and plaques characteristic of the disease. The inflammation process that creates these metabolites can be triggered by numerous stimuli, including infections that precede the onset of Alzheimer's disease by a significant amount of time — perhaps years. Traumatic head injuries, for example, are a major risk factor for later developing Alzheimer's disease. Inflammation is increasingly seen as playing a role in neurodegenerative diseases.
Zhang, Q., Powers, E.T., Nieva, J., Huff, M.E., Dendle, M.A., Bieschke, J., Glabe, C.G., Eschenmoser, A., Wentworth, P.Jr., Lerner, R.A. & Kelly, J.W. 2004. Metabolite-initiated protein misfolding may trigger Alzheimer's disease. Proceedings of the National Academy of Sciences, 101 (14), 4752-7.