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Spinal Cord Injury May Increase the Risk of Alzheimer’s Disease

It may be surprising to some people to learn that physical injuries can contribute to neurodegenerative diseases. In mice, traumatic brain injuries have been previously shown to induce an Alzheimer’s-like condition, complete with amyloid plaques and neuroinflammation. In a study published this week in the journal Spinal Cord, researchers from the National Taiwan University investigated whether a similar connection exists between spinal cord injuries (SCI) and Alzheimer’s disease.

The researchers utilized medical records from Taiwan’s National Health Insurance Research Database. Their analyses included 9,257 individuals with an SCI and 37,028 non-SCI individuals, with an average age of approximately 63 years. When selecting the subjects for the study, the researchers applied an algorithm that would correct for the effects of other Alzheimer’s disease risk factors, such as age, sex, and cardiovascular health.

Over the course of a three-year period, a total of 25 SCI inviduals and 57 non-SCI individuals were diagnosed with Alzheimer’s. These numbers are quite low, possible due to the difficulty in diagnosing Alzheimer’s with high certainty, since its symptoms are similar to other forms of dementia. Cumulatively, the incidence of an Alzheimer’s diagnosis during the three-year study period was 71% higher in people with a SCI compared to people without a SCI. (I want to emphasize that this does not mean SCI patients are 71% more likely to get Alzheimer’s over their entire lifetime; this number only applies to the three-year period examined in this study.)

This figure from the paper shows the incidence of Alzheimer’s disease over a three-year period. The SCI individuals had an increased risk of Alzheimer’s than the non-SCI individuals.

This study is the first large-scale, longitudinal analysis to demonstrate a correlation between SCI and Alzeimer’s disease. Future research is warranted to determine what might be causing this connection. The authors suggested several possible explanations. It has been previously shown that tau and the amyloid precursor protein are deposited throughout the spinal cord following a SCI. These proteins are both closely linked to the pathogenesis of Alzheimer’s disease, so this could be a possible disease mechanism. Another possibility is that the widespread inflammation triggered by a SCI could perturb the delicate chemistry of molecules within the brain.

There are several important caveats to note with this study. For one thing, while the researchers accounted for health-related Alzheimer’s risk factors, including various medical conditions like diabetes and stroke, their records did not include information about lifestyle-related risk factors, such as smoking or exercise. These factors could have potentially skewed the analysis. Also, since the follow-up period was only three years, the data does not give us information about any longer-term effects of SCI. Finally, while the total sample size was large, only a small subset of subjects were diagnosed with Alzheimer’s, reducing the statistical power of the analysis. Future studies will need to address these problems in order to provide further insight into the emerging connection between SCI and Alzheimer’s disease.

 

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A Third of Dementia Cases Could Be Preventable

Dementia is caused by a variety of genetic, environmental, and lifestyle factors. A new study published in The Lancet offers hope that many of us could avoid dementia by making healthier choices for our brains. The study was conducted by the International Commission on Dementia Prevention, Intervention, and Care, a panel of 24 experts assembled to conduct a review and meta-analysis of existing dementia research. The scientists concluded that with a cure to Alzheimer’s disease likely to still be years away, the best approach is to focus on prevention.

Among the contents of the report was a series of recommendations for reducing the risk of dementia. They identified nine modifiable risk factors that are responsible for 35% of dementia cases. These factors seem to act primarily at a particular stage of life:

  • Childhood: Low educational attainment
  • Mid life: Hypertension, obesity, hearing loss
  • Late life: Depression, diabetes, physical inactivity, smoking, social isolation

The researchers argue that by addressing these modifiable risk factors, a third of dementia cases could be prevented. They showed that by reducing the prevalence of these risk factors by only 10%, more than 1 million dementia cases could be avoided worldwide. The report also included several recommendations for dementia management and care. These included pharmacological treatment of dementia patients at all disease stages, individualized care tailored to each patient, managing neuropsychiatric symptoms with social or environmental interventions, and providing support for caregivers, who are at an increased risk of depression and other health problems.

A press release of the data presented at the Alzheimer’s Association International Conference noted that there are many other likely risk factors associated with dementia, including diet, air pollution, and sleep. These were not mentioned in the report due to a lack of conclusive research, but it is likely that even more dementia cases could be preventable with these other factors considered. For more information on brain health and dementia prevention, see How to Reduce Your Dementia Risk in 2017.

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Image Source: Keck Medicine of USC

 

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How to Reduce Your Dementia Risk in 2017

2017 is almost upon us, and that means it’s time for New Year’s resolutions. Many of us resolve to lose weight, quit smoking, or spend less money. However, I’d like to suggest a new resolution for you to try out this year: improving the health of your brain. Though Alzheimer’s disease and other dementias are not completely preventable, there are a variety of steps you can take to substantially reduce your risk. The younger an age you start implementing these simple lifestyle changes, the more benefits you will reap, but it’s never too late to start protecting your brain.

Tip #1: Improve Your Oral Hygiene

Nearly half of all adults in America have periodontitis, a severe form of gum disease that gradually destroys the bone sockets holding your teeth in place, resulting in tooth loss. Recent evidence suggests that the bacteria  that cause periodontitis may be able to enter the brain, and their presence has been correlated with reduced cognitive function. Protect your mouth and your brain by brushing twice per day, flossing once per day, and visiting the dentist twice per year. To read more see How Oral Hygiene Protects Your Brain From Dementia

Tip #2: Get Your Daily Dose of Vitamin D

A recent meta-analysis concluded that vitamin D deficiency is a strong risk factor for dementia. Vitamin D is not easily obtained through food, but our bodies can synthesize it when our bare skin (without sunscreen) is exposed to sunlight. The time required to meet your 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.

Tip #3: Reduce Your Risk of Diabetes

Nearly 30 million Americans (around 10% of the total population) have diabetes, and another 86 million are prediabetic. People with diabetes have an approximately 54% higher risk of Alzheimer’s disease. According to the NIH’s Diabetes Prevention Program, even people at high risk of diabetes can prevent the disease through a combination of weight loss (5-7% of your total body weight), a healthy diet, and regular exercise. The National Diabetes Education Program offers lots of great tips for transitioning to a healthier lifestyle. To read more see Alzheimer’s Disease: Diabetes of the Brain?

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The impact of dietary choices on the risk of type 2 diabetes. Source

Tip #4: Get Your Brain Health Checkup

Healthy Brains is a website created by the Cleveland Clinic Lou Ruvo Center for Brain Health. The website is centered around the six pillars of brain health: physical exercise, food/nutrition, medical health, sleep/relaxation, mental fitness, and social interaction. One of my favorite parts about the site is the Brain Health Checkup, a free quiz that takes around 20 minutes to complete. After taking the quiz, you can read personalized tips on how to improve your brain health. Click here to check it out.

 Tip #5: Get Enough Sleep

You’ve probably heard a million times about the health consequences of sleep deprivation, but did you know that it may also increase the risk of Alzheimer’s? The Baltimore Longitudinal Study on Aging found that people over the age of 70 who report little sleep or low-quality sleep have higher levels of amyloid beta (a toxic protein linked to Alzheimer’s disease) in their brains. Additionally, a 2013 study found that amyloid beta and other toxic substances can actually be flushed out of the brain during sleep.

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Age-based recommendations from the National Sleep Foundation. Source

Tip #6: Adopt the Mediterranean Diet

The Mediterranean diet is often praised for its cardiovascular benefits, but recent studies show that it’s also great for your brain. This diet, commonly consumed in places like Italy and Greece, has been linked to a reduced risk of Alzheimer’s and improved cognitive function in older adults, as well as a longer average lifespan. The Mediterranean diet is characterized by high consumption of plant-based foods including fruits, vegetables (especially leafy greens), whole grains, legumes, and nuts. Red meat and dairy are consumed no more than a few times per month, replaced instead by poultry or fish.

Tip #7: Be Socially Active

Engaging in social interactions is a great way to stimulate your brain, and having a large social network is correlated with a reduced risk of dementia. While a causal relationship is difficult to determine, social engagement has also been shown to improve overall quality of life, especially for older adults. For introverts, there are many ways to be socially active besides going out with friends. These could include adopting a pet, conversing on social media websites, volunteering, or joining a community group.

Tip #8: Get More Exercise

This one might already on your list of resolutions, but here’s one more reason to get off the couch. Studies have consistently shown that people who get regular physical exercise have a substantially lower risk of Alzheimer’s disease and other dementias. Aerobic exercise, such as walking, jogging, biking, or dancing, seem to have the biggest protective effect on brain health. The CDC recommends that adults get 2.5 hours of moderate aerobic activity or 1.25 hours of vigorous aerobic activity each week, plus at least two sessions of muscle strength training.

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The many benefits of exercise for your brain. Source

Tip #9: Protect Your Brain From Injuries

Traumatic brain injuries (TBI’s), which may be the result of contact sports, falls, or car accidents, affect nearly 1.7 million Americans each year. TBI’s, including mild injuries that do not necessarily cause a concussion, have been repeatedly linked to an increased risk of Alzheimer’s disease. TBI’s are especially damaging in children, whose brains are still in the process of developing. Minimize your risk of a TBI by wearing a helmet when playing contact sports, installing house fixtures to protect from falls, and always wearing a seatbelt while driving.

Tip #10: Never Stop Learning

Lifelong education, whether formal or informal, is vital for keeping your brain active and maintaining proper cognitive function. Formal education could include taking classes at a nearby community college or online, teaching yourself a new language, or learning to play an instrument. More informal types of mental stimulation could include reading, doing crossword puzzles, social interaction, or attending musical or theatrical performances.

 

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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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The Genetics of Alzheimer’s Disease

If you’d asked me at age sixteen what my life’s dream was, I’d say it was to discover the Alzheimer’s gene. Statements like that one would make any geneticist cringe, or chuckle, or both. It’s a common misconception that one “bad” gene causes Alzheimer’s disease, and that discovering this gene would lead to a cure. The fact of the matter is that Alzheimer’s disease, and most other diseases, are so much more complicated than a single gene. There are a multitude of genes involved, as well as an entire spectrum of non-genetic influences. To try and make sense of this confusing topic, I’ve written this article as a brief overview of the genetics of Alzheimer’s disease.

Note: If you’re not familiar with the science of Alzheimer’s, you may want to look at Alzheimer’s Disease: A general overview to provide a bit of background.

The Amyloid-Beta Protein

Genes encode proteins, and so to understand the role of genetics in Alzheimer’s, we need to first look at the proteins involved. Senile plaques are considered one of the main hallmarks of Alzheimer’s disease. These toxic protein clumps accumulate in the brain over many years and eventually lead to the death of neurons, causing the brain to physically shrink. They form when a protein called amyloid-beta becomes “sticky” and begins to adhere to itself, forming large star-shaped clumps.

Amyloid-beta begins as a longer protein called amyloid precursor protein (APP). APP is usually cut by enzymes called secretases to form a non-sticky version of amyloid-beta that is 40 amino acids long. However, if APP is cut by a different set of secretases, a longer version of amyloid-beta with 42 amino acids is formed. This longer form is what sticks together to form senile plaques in Alzheimer’s disease [1].

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Formation of the longer amyloid-beta protein by beta-secretase and gamma-secretase. Source: https://www.rndsystems.com

Familial Alzheimer’s Disease

Alzheimer’s disease is divided into two forms. Approximately 5% of cases are of the familial, early-onset form. This type of Alzheimer’s typically affects individuals in their mid-forties and fifties. There are three genes known to be involved with familial Alzheimer’s disease: APP, PSEN1, and PSEN2. APP, as I described above, is the precursor to amyloid-beta, and so certain mutations can make it prone to the cleavage pathway that results in the sticky 42-length protein. Similarly, PSEN1 and PSEN2 are believed to affect the gamma-secretase complex that cleaves APP into amyloid-beta.

Mutations in these three genes are autosomal dominant. This means that only one copy of the mutation is needed to cause the disease, and that carriers have a fifty-percent chance of passing on the gene to each of their children. The mutations also tend to have high penetrance, meaning that their effects cannot be readily altered by environmental factors–i.e., having the mutation nearly always leads to the disease [2], [3].

Sporadic Alzheimer’s Disease

In contrast to the relatively simple genetics of familial Alzheimer’s, late-onset sporadic Alzheimer’s disease (which makes up 95% of cases) is far more complex. The only gene that has been conclusively identified as a risk factor is apolipoprotein E, abbreviated as apoE. We still aren’t sure exactly how apoE affects the brain, but the main hypothesis is that it’s involved with clearing away amyloid-beta before it can accumulate to toxic levels. There are three major versions of this gene: apoE2, apoE3, and apoE4. Having one copy of the apoE4 allele increases the risk of Alzheimer’s by 3 times, while having two copies increases the risk by nearly 15 times. Conversely, having at least one copy of the apoE2 allele reduces the risk of Alzheimer’s [2][4].

It is important to note that unlike the genes involved with familial Alzheimer’s, the apoE alleles are not highly penetrant. Approximately 1 in 5 people have at least one copy of apoE4, yet the majority of them never develop Alzheimer’s. Additionally, there are many people who develop Alzheimer’s without possessing apoE4. The allele increases the risk of developing the disease but is far from a guarantee [2][4]. Overall, it’s estimated that apoE accounts for less than 20% of the genetic risk for sporadic Alzheimer’s [5], [6].

So where does the other 80% come from? The answer gets even more complicated here. There are dozens of genes that are weakly correlated with overall risk, age of onset, rate of progression, or other disease variables. Individually, each of these genetic variants has only a tiny effect, but when combined, each person’s unique combination of variants creates a genetic profile that influences his or her risk of developing the disease (see A New Approach to Predicting Risk of Alzheimer’s Disease). The majority of these weakly-associated genetic variants have yet to be identified [3].

Non-Genetic Factors

In familial Alzheimer’s, there is little that a person can do to prevent the disease if he or she has inherited the gene. However, only 24-33% of a person’s risk for sporadic Alzheimer’s disease is attributable to genetics alone [5], [6].  The remaining risk is modulated by non-genetic factors, including medical conditions, diet, and lifestyle choices. A recent meta-analysis identified 13 non-genetic factors that significantly increase the risk for Alzheimer’s disease, including smoking, being overweight in midlife, cardiovascular disease, low education, and depression. In addition, they identified 23 factors that reduce the risk of Alzheimer’s, including a healthy diet, physical activity, mental stimulation, and certain medical conditions [7].

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Non-genetic protective and risk factors for Alzheimer’s disease. Source: Xu et al., 2015.

Conclusion

It was once thought that we couldn’t change our brains after birth, but the discovery of neuroplasticity revolutionized the field by showing us that our daily actions can have enormous impacts on the structure and function of our brains. Similarly, the growing study of epigenetics (meaning “above genetics”) proves that we are not at the mercy of our genes. Though we are born with a set DNA sequence, the choices we make throughout our lives determine which genes are turned on or off, a process that can significantly influence our risk of disease. We may not be able to change the genetic risk coded into our DNA, but we can all help protect our brains from Alzheimer’s disease through simple lifestyle choices.

 

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A New Approach to Predicting Risk of Alzheimer’s Disease

Background

An individual’s risk for Alzheimer’s disease is affected by a variety of genetic and environmental factors. While the causes of early-onset Alzheimer’s are well understood, the genetic factors underlying late-onset Alzheimer’s disease (LOAD), which makes up 95% of total cases, are less clear. The APOE4 allele is considered the major risk factor for this form of Alzheimer’s, as it can increase your risk by 2-3 times if you have one copy of the allele or up to 15 times if you have two copies. APOE4 does not guarantee that an individual will develop LOAD, and researchers have been searching for other genes that may be involved. (For more background see The Genetics of Alzheimer’s Disease).

Genome-wide association studies, which systematically analyze the 0.1% of DNA sequence that varies between individuals, have linked at least 21 other genes to an increased risk of LOAD. Individually, each of these genes has only a small influence in comparison to APOE4, often increasing one’s risk by only a few percentage points. However, when many of these small genetic risk factors are combined, they can greatly affect an individual’s chances of developing LOAD.

Overall, studies suggest that approximately 33% of an individual’s risk for developing LOAD is attributable to genetics, with the rest being due to lifestyle choices and environmental factors. Of this, APOE and the 21 already-identified genes account for less than 25% of the genetic risk, suggesting that the majority of genetic risk factors for Alzheimer’s disease remain unknown.

New Results

In a recent study published in the journal Neurology, a group of researchers from the Alzheimer’s Disease Neuroimaging Initiative searched for other genes, outside of the 21 already identified, that could also act as slight risk factors for Alzheimer’s. They used data collected from the International Genomics of Alzheimer’s Project to compute polygenetic risk scores, or PGRS, for both young and elderly adults who did not have dementia. Each person’s PGRS was calculated using his or her unique combination of small genetic risk factors (including many that were not statistically significant in genome-wide association studies) in order to estimate the genetic risk for LOAD. The researchers then analyzed whether PGRS were associated with biological markers of preclinical Alzheimer’s disease.

In elderly subjects who did not have dementia, high PGRS was associated with poorer memory, smaller volume of the hippocampus (the part of the brain that helps us form new memories), and increased levels of toxic beta-amyloid in the brain. High PGRS in these individuals also correlated with an increased rate of cognitive decline and a greater probability of later being diagnosed with Alzheimer’s disease. The researchers also computed PGRS for younger subjects under the age of 35. They found that a high PGRS was associated with reduced hippocampal volume, similarly to the older subjects.

Together, these results suggest that more genes besides the currently-identified 21 may need to be considered when evaluating an individual’s risk for LOAD. The researchers plan to repeat this study using a larger sample size to verify the results. Future studies also will track younger subjects to see if PGRS can predict their risk for Alzheimer’s as they age, and compare these results to less comprehensive systems of genetic prediction. The hope is that by refining PGRS, we may one day be able to develop better genetic tests for young people that yield more accurate predictions of future Alzheimer’s risk.

 

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