Monthly Archives: October 2016

A New Possible Mechanism for the Development of Alzheimer’s Disease


Alzheimer’s disease is characterized by the buildup of toxic protein species in the brain. One of these proteins is tau. Tau normally is involved with stabilizing the cytoskeleton that gives neurons their structure. However, in people with Alzheimer’s disease, certain enzymes attach too many phosphate groups to tau. Molecules of this hyperphosphorylated tau can stick to each other to form tangles of fibers that accumulate inside of neurons.

It was originally assumed that these tau tangles contributed to neuronal death in Alzheimer’s disease. However, it has since been discovered that less than 17% of neurons in an Alzheimer’s brain contain tangles, even in the most advanced disease stages. Additionally, it was recently shown that the tangles are not associated with memory deficits or neuronal death in a mouse model. This has led some researchers to speculate that the soluble form of tau, which does not accumulate into tangles, might actually be the toxic species.

New Results

In a study published last week in Nature Medicine, researchers uncovered a possible mechanism for the toxicity of soluble tau. At the time, they were studying mice with a mutation that causes them to express high levels of tau. The researchers noticed that a particular fragment of tau called ∆tau314 (named so because it had been cleaved after the 314th amino acid) was more abundant in the mice that had greater memory impairment. They then looked at human brain tissue from 85 elderly subjects and found that tau fragments similar to ∆tau314 were present at significantly higher levels in cognitively impaired subjects compared to non-impaired controls. They demonstrated experimentally that this fragment was soluble and did not form the large tau tangles.

Subsequent experiments determined that an enzyme called caspase-2 was capable of cutting the ∆tau314 fragment from full-length tau. When they reduced the levels of caspase-2 in the brains of their Alzheimer’s mice, the levels of ∆tau314 decreased and the mice showed complete reversal of cognitive impairment.

The researchers were also able to determine the mechanism by which ∆tau314 leads to cognitive impairment. Previous studies had shown that in Alzheimer’s disease, tau improperly localizes to dendritic spines, the part of the neuron where it receives communicative inputs from other neurons. These communication sites can malfunction when too much tau is present. The researchers created mice expressing a form of tau that was resistant to cleavage at the 314th amino acid. They found that this form of tau did not localize to dendritic spines. Additionally, the mice did not experience any cognitive impairment or neurodegeneration, despite expressing high levels of this modified tau.

The main conclusion of this study was that in order for tau to induce the pathology of Alzheimer’s disease, it must first be cut at the 314th amino acid by caspase-2. This is an intriguing result, as it suggests that caspase-2 might be a useful therapeutic target for future drug research. In theory, if we can prevent caspase-2 from cutting tau, this could in turn prevent tau from causing malfunctions in dendritic spines. In addition, this study provides further support for the hypothesis that soluble tau, rather than insoluble tau tangles, is the more harmful species in Alzheimer’s disease.

An important caveat of this study is that it was performed almost exclusively on mice. These mice are only a simulation of human Alzheimer’s disease, and thus the same mechanisms may not translate to humans. Though significantly higher levels of ∆tau314 were found in cognitively impaired human brains, further research is needed to determine whether blocking caspase-2 cleavage of tau offers the same benefits in humans as it does in mice.

Additionally, the mice in question only simulated the tau pathology of Alzheimer’s. Tau is only one aspect of human Alzheimer’s disease. Other relevant pathologies include beta-amyloid plaques, neuropil threads, and neuroinflammation. Thus, it seems unlikely that eliminating the toxicity of tau could entirely reverse the disease in humans. A more likely scenario is that a caspase-2 drug therapy might be combined with other drugs that target the other pathological agents.

Despite these caveats, this paper represents an exciting development in Alzheimer’s disease research. Only time can tell whether it will translate to human drug candidates down the road.


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Air Pollution, Aluminum, and Vitamin D Deficiency Linked to Dementia Risk

A recent meta-analysis published in BMC Geriatrics analyzed 60 human studies of environmental risk factors for dementia. The authors of the paper applied statistical analysis based on the overall quality of each study (i.e., the highest quality papers had a larger sample size and robust measures of exposure and outcome) in order to synthesize their results into broader conclusions. Based on these calculations, they assigned each risk factor a score based on the strength of the evidence for its involvement in dementia. A “strong” score indicates solid evidence linking a risk factor to dementia, while “moderate” or “weak” scores suggest that more research needs to be done before a conclusion can be drawn.

Air Pollution

Air pollution was concluded to be a significant risk factor for dementia based on the results of eight independent studies. Sources of air pollution with strong scores included nitrogen oxides, particulate matter (such as dust, smoke, and soot), and ozone, while carbon monoxide and environmental tobacco smoke received a moderate score. Major sources of air pollution include cars, construction sites, industrial smokestacks, and power plants. Individuals living in urban areas may want to consider investing in home air filters in order to reduce their exposure to air pollution.

Metals and Micronutrients

If you’ve read my article on the role of metals in Alzheimer’s disease, you know that certain metals are correlated with an increased risk of Alzheimer’s, though the evidence is still not conclusive enough to say for sure whether they contribute directly to the development of dementia. The meta-analysis confirmed this interpretation. Most of the metals in the analysis (including lead, copper, iron, and zinc) were given a weak score. The only metals to earn a moderate score were aluminum and arsenic. My article mentioned above includes some easy tips for reducing your exposure to aluminum and other metals.

In addition, two micronutrients were identified as potential dementia risk factors when consumed above recommended dosages. Selenium, which is found in meat, seafood, dairy products, and mushrooms, scored moderate on the risk scale. Silica, a mineral found at varying concentrations in drinking water, scored high risk. Though small amounts of both these minerals are important for health, it may be best to avoid taking them in supplement form (unless instructed by a physician) in order to avoid over-consumption.

Occupational Exposure

The review also analyzed studies on exposure to potentially-harmful substances in the workplace. Pesticides and fertilizers were identified as high risk factors, a worrying find for those in the agricultural industry. This may explain why children living in rural areas are at higher risk for dementia as adults, which was concluded in a previous meta-analysis by the same authors. Exposure to industrial solvents or degreasers was also a high risk factor. The occupational factors rated at moderate risk included metals, diesel motor exhaust, and (strangely enough) electromagnetic fields. The latter finding remains highly controversial.

Vitamin D

The evidence analyzed in this study identified vitamin D deficiency as a strong risk factor for dementia. This finding was supported by three independent studies of more than 15,000 subjects in total, though one small study involving 40 subjects did not find an association. Vitamin D is not easily obtained through food. However, our body can synthesize vitamin D when our bare skin (without sunscreen) is exposed to sunlight. The time required to meet our daily dose of vitamin D depends on your skin tone, the amount of sunlight available, and how much skin you have exposed. On a sunny summer day, 10-15 minutes is often enough. You may want to consider taking vitamin D supplements during the winter, if you live in an often-cloudy area, or if you do not go outside every day.

Concluding Remarks

The authors of this paper noted several sources of bias in their meta-analysis. An important consideration is that the studies have been conducted almost exclusively in high-income countries, despite the highest rates of dementia occurring in low- to middle-income countries. Additionally, since none of these studies measured exposure at more than one time point, the data can’t predict whether any critical periods exist for exposure to these risk factors. In other words, exposure may be more harmful during old age than childhood, or vice versa. Finally, as with any observational study, it’s important to keep in mind that these risk factors may not all be causal (see How to Be a Smart Consumer of Science News).

Despite these sources of error or bias, the exposures identified as high or moderate risk factors for dementia should not be taken lightly. Some of them are easier to avoid than others, but it makes sense that we should all take whatever steps we can to reduce our risk of dementia.


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Caffeine May Protect Older Women from Dementia

Coffee and tea have long been applauded for their strong antioxidant properties and ability to combat inflammation. During the past few years, several experiments using animals have suggested that the benefits of these beverages may come primarily from their caffeine content. For example, a 2012 study reported the results of administering caffeine to mice that had a genetic predisposition for Alzheimer’s. As a result, these mice experienced reduce cognitive decline, amyloid-beta plaque levels, and rates of neuronal death. However, studies on humans have been less consistent, with some reporting reduced rates of dementia among high consumers of caffeine, and others finding no relationship at all.

A study published last week in the Journals of Gerontology: Medical Sciences attempted to end the caffeine debate once and for all. The study involved a cohort 6,467 women between the ages of 65 and 80 who were part of the Women’s Health Initiative Memory Study. At the beginning of the study, the women were asked to report their normal daily consumption of caffeine. Based on this information, the researchers categorized them as low (<50th percentile) or high (>50th percentile) caffeine consumers. The low-caffeine group consumed an average of 64 mg per day, which is the equivalent of 5 oz of coffee (half of a large mug). The high caffeine consumers consumed an average of 261 mg per day, the equivalent of 22 oz of coffee (2-3 large mugs). The women’s caffeine consumption appeared to stay fairly constant during the course of the study.

After an average of seven years, each woman underwent a cognitive assessment to determine the presence of dementia. Women who consumed high amounts of caffeine were 26% less likely to be diagnosed with probable dementia or cognitive impairment in the follow-up assessment. They also had a reduced risk of Parkinson’s disease and scored better on a test of global cognitive function called the Modified Mini Mental State Exam (MMMSE).

Notably, the researchers pointed out that the association between cognitive impairment and caffeine intake was dampened when baseline MMMSE scores were taken into account. In other words, the high consumers of caffeine may have had higher cognitive function than the low caffeine consumers to begin with. Thus, it makes sense that they’d have reduced cognitive impairment at the follow-up, since they initially had a “head start,” regardless of their actual caffeine consumption. Future studies will need to investigate this possible confounding variable.

This study was fairly homogenous, with all of the subjects being postmenopausal women who were generally healthy and well-educated. Accordingly, the results can’t be generalize to other populations. There is also the possibility that the women’s self-reported caffeine intake may have differed from their true intake, especially since caffeine intake was only monitored based on coffee and tea, thus excluding soda and other caffeinated foods/beverages.

Overall, this study is not sufficient to conclusively say whether caffeine is protective against dementia, despite the recent popular science headlines claiming otherwise. Since in general the health benefits of coffee and tea seems to outweigh any negatives, it’s probably fine to continue consuming them if you do so normally (within the advice of your doctor, of course). However, there’s not enough evidence yet to recommend increasing caffeine intake for neuroprotective purposes.


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The Role of Metals in Alzheimer’s Disease

Small amounts of certain metals, such as zinc, copper, and iron, are necessary for our bodies to function properly. These are referred to as biometals. Other metals like aluminum are not needed for survival but can be tolerated by the body in low doses. However, for reasons that remain unclear, studies have shown that patients with Alzheimer’s disease often have an imbalance of these metal ions in their brains. Abnormally high concentrations of the aforementioned metals have been found inside of amyloid-beta plaques, the toxic protein deposits that are the hallmark of the Alzheimer’s brain [1]. This observation led some scientists to propose the metal theory of Alzheimer’s disease, which suggests that regular exposure to metals can lead to the development of Alzheimer’s [2]. In this article I briefly will evaluate the evidence for and against the metal theory, and describe how it may affect your life.


Aluminum was the first metal that was proposed as a possible cause for Alzheimer’s disease, leading to panic about the aluminum found in soda cans, cookwear, and many processed foods. Back in 1965, researchers showed that rabbits injected with aluminum developed toxic tau fibrils in their brains [3] [4]. Multiple studies have since verified this finding in mice, rats, cats, and monkeys [5].

More than sixty years after the initial experiments, we still have not come to a consensus on whether aluminum exposure can lead to Alzheimer’s. Studies have demonstrated that only levels of aluminum far exceeding those found in the body are capable of promoting amyloid-beta aggregation [6]. In addition, multiple studies have failed to find an association between exposure to aluminum (within normal safety guidelines) and risk of Alzheimer’s. On the other hand, experiments in which rats are chronically exposed to aluminum show accumulation of aluminum in their brains, particularly in the hippocampus (the brain’s memory center). These rats experienced memory impairments as a result of their aluminum exposure [5]. Overall, it’s possible that aluminum contributes in some form to the pathology of Alzheimer’s, but there is not enough evidence to conclude a causative relationship.

Zinc, Copper, and Iron

The biometals zinc, copper, and iron play a variety of important roles in the brain, including cell signaling and neuroplasticity. However, too much of these metals may be harmful for our health. In cell cultures, physiological concentrations of zinc and iron (possibly copper as well, but this is less clear) can promote the formation of amyloid-beta plaques [7]. In addition, all three of these biometals can accelerate the aggregation of tau, another toxic protein found in Alzheimer’s disease. Copper and iron are also believed to contribute to oxidative stress [8]. Oxidative stress is a chemical process involving free oxygen radicals that gradually leads to cell damage and aging; the reason antioxidants are good for you is because they get rid of these free oxygen radicals.

Despite these results, there’s more to the biometals than meets the eye, particularly for zinc. The so-called “zinc paradox” arises from seemingly-contradictory evidence suggesting that zinc can also be neuroprotective in Alzheimer’s disease. When zinc binds to amyloid-beta, it changes the protein’s shape such that its toxicity is reduced. Thus it seems that zinc can stimulate amyloid-beta aggregation but also reduces the toxicity of these aggregates [9]. More research is needed to conclusively determine whether zinc is helpful or harmful in the long-run.

As a rule, most researchers agree that these biometals are likely involved in some way in the pathogenesis of Alzheimer’s disease, but there’s debate on whether they play a directly caustive role. It’s also unclear whether risk can be modulated by dietary or environmental exposure to these metals. For example, certain neurological events (such as a stroke or traumatic brain injury) can increase the levels of metal ions in the brain, so it’s possible that internal rather than external sources are to blame [10].

Other Metals

Though the four metals described above have been the main focus of Alzheimer’s metallobiology research, it’s possible that others could be involved as well. A small number of studies have drawn connections between Alzheimer’s and lead, cobalt, cadmium, and manganese, among others. Though there is not nearly enough evidence to make any definitive claims regarding the involvement of these metals in Alzheimer’s, they raise the possibility that the onset of Alzheimer’s could be exacerbated by chronic exposure to multiple metals simultaneously [11].

Metal Chelators as Alzheimer’s Drugs

If metals are indeed involved in the development of Alzheimer’s, it follows that metal chelators could be useful in the treatment of Alzheimer’s disease. Chelators are compounds that bind to metal ions and help to expel them from the body. Several types of chelators have been tested in animal and human trials for Alzheimer’s. Many of these drugs showed promise, but none have been approved for patient use, most often due to severe side effects. Current research is working to improve these early drugs and make them safer for widespread use [8].

Reducing Exposure to Metals

At present, there simply isn’t enough evidence to conclusively say that exposure to common metals can lead to Alzheimer’s disease. The most likely possibility is that metal exposure alone is not sufficient to cause Alzheimer’s, but it may contribute to disease pathology in combination with other factors including genetics, diet, exercise, and mental stimulation.

However, this does not necessarily mean that we shouldn’t take steps to reduce our exposure to metals. Just because there’s not enough evidence now, doesn’t mean more won’t arise in the future. Reducing daily exposure to metals is simple enough that no harm is done even if they turn out to be innocuous in the end. Here are a few easy tips you can consider [12]:

  • Unless instructed by a doctor, avoid vitamins or supplements contain very high levels of zinc, copper, or iron. Most people who consume a balanced diet have no need for biometal supplements. Shellfish, meats, and nuts are the best dietary sources of biometals. If you do choose to take supplements, do not exceed 100% of the daily recommended value.
  • If your drinking water comes from copper pipes or faucets, run the water for 15-30 seconds each morning before drinking.
  • Reduce your intake of red meat and highly processed foods.
  • The levels of aluminum or copper in cookwear are generally considered safe, but may increase when they are used to cook highly acidic foods (such as spicy foods or tomato sauce). Consider switching to glass or stainless steel.
  • Limit your use of antacids and aspirins that contain aluminum.
  • When baking, use parchment paper instead of foil.
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