Category Archives: Alzheimer’s In the News

A Causal Link Between Alzheimer’s Disease and Cancer

Though they may seem like unrelated diseases, cancer and Alzheimer’s disease are more closely linked than you’d expect. As I’ve discussed previously on the blog, scientists have been aware for nearly 15 years that these two conditions are inversely correlated. In other words, cancer survivors have a lower risk of later developing Alzheimer’s disease, and vice versa.

According to one meta-analysis, Alzheimer’s patients have a 42% reduced risk of developing any kind of cancer in their lifetime, while cancer survivors have a 37% reduced risk of Alzheimer’s disease. Notably, this correlation is not caused by decreased life expectancy or different lifestyle choices, as the analysis took these factors into account in their calculations.

While those numbers look pretty convincing, we must be careful when interpreting the results of observational studies. A scientist’s favorite mantra is “correlation does not imply causation.” In other words, based on these studies alone, we have no way to know whether cancer directly protects against Alzheimer’s disease, Alzheimer’s directly protects against cancer, or some unknown third factor is linking the two diseases indirectly. We can’t determine a causal relationship from observation alone.

However, a recent study published in Scientific Reports attempts to address this dilemma. Researchers from the University of Cambridge used a technique called Mendelian randomization to determine causality. Essentially, this involves searching for genetic variants that are known to increase the risk of cancer, and then determining whether those same variants also decrease the risk of Alzheimer’s. By probing at the genetic level, this technique allows researchers to directly determine whether cancer is protective against Alzheimer’s.

Using data from public repositories, the authors determined that several genetic variants involved in cancer risk are protective against Alzheimer’s. Overall, a 10-fold (1000%) higher genetic risk for developing cancer results in a 2.5% reduced risk of Alzheimer’s. That may seem like a small reduction, but keep in mind that this represents only the genetic component of risk. Since both cancer and Alzheimer’s are complex diseases and heavily influenced by non-genetic factors, these numbers encapsulate only a small portion of an individual’s overall risk.

Importantly, this study is the first to show a causative link (rather than merely a correlation) between Alzheimer’s disease and cancer. The study’s lead author, Sahba Seddighi, stated, “Our results offer novel possibilities for targetable pathways in Alzheimer’s disease—which remains without a cure, despite a rapidly growing aging population—and call for a deeper understanding of the underlying mechanisms behind this relationship.”

So what does this link really mean? In a way, it makes some intuitive sense: cancer is the result of uncontrolled cell growth and proliferation, while Alzheimer’s is associated with cell death and degeneration. But what genetic interactions and cell signaling pathways are involved remains unknown.

In the meantime, by shedding new light on the genetic underpinnings of Alzheimer’s, the study brings a new insight to the field, which will hopefully bring scientists one step closer to finding a cure.

 

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Neurons Changing their DNA Could Lead to Alzheimer’s Disease

A recent study finds that neurons can spontaneously change the sequence of a gene called APP, which is involved with Alzheimer’s disease.

In most cases, the DNA that you’re born with stays the same throughout your entire life. However, according to a paper recently published in Nature, neurons can randomly change their own DNA sequence, which may contribute to the development of Alzheimer’s disease.

The study was led by Dr. Jerold Chun’s research group at the University of California San Diego and the Sanford Burnham Prebys Medical Research Institute. Dr. Chun’s lab and others have previously shown that adult neurons can alter their own DNA sequence. As a result, different neurons inside your brain can have their own unique genomes, a phenomenon known as genomic mosaicism. This is distinct from epigenetic modifications, which can turn genes on or off but do not change the actual genetic sequence.

Genomic mosaicism, which occurs by a seemingly random process, can range in size from a single nucleotide to entire chromosomes. These changes tend to accumulate as we age, which led many scientists to wonder if they could be related to neurodegenerative diseases.

Our Mosaic Brains and Alzheimer’s Disease

In their recent Nature paper, Dr. Chun’s group investigated a single gene called Amyloid Precursor Protein, or APP for short. APP is the precursor to amyloid-beta, a toxic sticky protein that builds up in the brains of people with Alzheimer’s disease. The researchers were curious whether different forms of the APP gene could exist throughout the brain.

Using postmortem brain samples from five people with sporadic Alzheimer’s disease, as well as five age-matched controls, they extracted DNA from individual neurons and sequenced the APP gene. They found that more than 6,000 variants of APP existed across different neurons.

Interestingly, the Alzheimer’s brains had far greater diversity of genetic variants than the healthy brains. This suggests that these unusual APP variants could be related to the development of Alzheimer’s. When they took three of these variants and expressed them in a cell culture, two of them resulted in cell death. In addition, the Alzheimer’s brains had several APP variants that have been linked to familial Alzheimer’s disease (a rare, genetic form of early-onset Alzheimer’s), while none of the healthy brains contained these variants.

Next, the researchers wanted to understand how all these different APP variants might arise in neurons. They used a hamster cell culture that was made to express the human APP gene. When they used chemicals to induce DNA double-stranded breaks, the cells began producing unique APP variants, just like human neurons. The researchers also showed that this process relies on reverse transcription, which converts an RNA sequence to DNA.

Impacts for Alzheimer’s, AIDS, and Memory

This discovery is a major shift for Alzheimer’s researchers. Previous anti-APP drug candidates have generally only targeted one form of the gene, and this work shows that a huge array of genetic variants can exist in our brains. We will certainly need to reconsider our strategy for Alzheimer’s therapies moving forward.

In addition, the link between genomic mosaicism and reverse transcription has some intriguing implications for HIV. Previously studies have shown that people with HIV who are over age 65 have a lower rate of Alzheimer’s disease than the general population. One explanation could be the anti-retroviral drugs that they take. These drugs prevent the HIV multiplying by inhibiting reverse transcription, a process that the virus requires for replication. An unintended consequence of this could be that these people do not develop the APP variants that are linked to Alzheimer’s. If this turns out to be the case, anti-retroviral drugs could possibly be used as a preventative measure for Alzheimer’s.

So far, none of this has addressed the reason why neurons are so prone to developing different APP variants. In the Nature study, another Alzheimer’s-related gene called PSEN1 did not have such a wide variety, suggesting that the mechanism is specific to APP. In addition, non-neuronal cells did not develop all these APP variants. A possible explanation could be that this process is important for memory formation. The authors suggest that storing so many unique version of APP could be a mechanism for memory storage and recall at the molecular level. This idea remains speculative, but it does have a kind of poetic irony to it: the gene responsible for forming memories could also destroy those memories as we age.

 

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Saliva Test for Alzheimer’s Disease Shows Encouraging Results

A small study suggests that saliva tests for amyloid-beta could be a useful method for diagnosing Alzheimer’s disease.

As we discussed in last week’s article, Alzheimer’s disease is notoriously difficult to diagnose, particularly in its early stages. Some estimates suggest that up to half of all Alzheimer’s diagnoses are incorrect. Currently-available tests for Alzheimer’s are often expensive and invasive, and in many cases they still can’t offer a completely accurate diagnosis.

In a recent study published in BMC Neurology, researchers investigated whether saliva could be used to detect the hallmarks of Alzheimer’s disease. The test quantifies levels of amyloid-beta, a toxic protein that accumulates in the brains of Alzheimer’s disease patients. Since detecting amyloid-beta inside the brain can be difficult, its levels in the saliva could be a useful proxy to aid in diagnosis.

The study included 15 patients with mild to moderate Alzheimer’s disease and 8 patients with normal cognition. The researchers collected saliva samples and used a highly sensitive protein test called an ELISA to quantify how much amyloid-beta each sample contained. They found that the saliva of Alzheimer’s patients contained more than twice as much amyloid-beta than that of the healthy patients.

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This figure from the paper shows that Alzheimer’s disease patients (represented as diamonds) all had higher salivary amyloid-beta levels than the normal patients (represented as squares). This relationship held true regardless of the patients’ age.

The results of this study suggest that the levels of amyloid-beta in the saliva could be a cheap and easy method for improving the accuracy of Alzheimer’s disease diagnoses. Since the current diagnostic methods require a spinal tap or blood sample, a saliva test could help encourage people to get tested for Alzheimer’s, considering an estimated 3-10% of individuals have a phobia of needles.

Due to the small sample size, this study needs to be repeated and expanded before we can draw broader conclusions. However, the preliminary results are encouraging and help to corroborate previous studies that have shown similar accuracy for these saliva tests. Perhaps in the future, diagnosing Alzheimer’s disease will be as simple as spitting into a tube.

 

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Computer Algorithm Diagnoses Alzheimer’s Disease from Brain Scans

Alzheimer’s disease is notoriously difficult to diagnose. Its symptoms are very similar to other conditions like Parkinson’s disease and vascular dementia (and may even occur simultaneously in some patients), making the task of diagnosing a patient’s condition challenging for physicians. An even more difficult task is predicting whether an individual with mild cognitive impairment will later progress to Alzheimer’s disease. Even advanced techniques have poor predictive power. Positron emission tomography (PET), a type of brain scan that measures the energy consumption of different brain regions, has only a 57.2% rate of accuracy.

To address this dilemma, a team of Canadian and South Korean scientists tested five different computer algorithms for their accuracy in diagnosing or predicting Alzheimer’s disease. Their results were published this week in Scientific Reports.

The researchers used a database of PET scans from the Alzheimer’s Disease Neuroimaging Initiative to train the computer models. Their study included 94 patients with Alzheimer’s disease and 111 age-matched healthy patients. They found that one model, called the Support Vector Machine with Iterative Single Data Algorithm (SVM-ISDA), could distinguish the Alzheimer’s patients from healthy controls with 80% accuracy.

The researchers then tested the performance of the computer models on three different PET scan databases. This time, rather than distinguishing Alzheimer’s disease from healthy patients, they wanted to see whether the models could predict whether individuals with mild cognitive impairment would develop Alzheimer’s disease within the next 3 years. Here the SVM-ISDA once again came out on top, though its predictive power was lower than for the previous task. The model predicted which patients would develop Alzheimer’s disease with an overall accuracy of around 51-59%. The other algorithms all had less than 50% accuracy.

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PET scanners like this one measure how much energy is consumed by different brain regions.

They next wanted to see whether the computer models could distinguish Alzheimer’s disease from two other types of dementia: Lewy body disease and Parkinson’s disease. These conditions are both frequency misdiagnosed as Alzheimer’s disease. They found that in patients who had Parkinson’s disease but had not yet developed dementia, the computer models could distinguish between Alzheimer’s and Parkinson’s. However, for patients with Lewy body disease or Parkinson’s disease dementia, the models could not distinguish them from Alzheimer’s disease.

The conclusion for this study was that the SVM-ISDA is the most accurate computer model for diagnosing and predicting dementia based on PET scans. However, while the model performed fairly well in diagnosis, its ability to predict Alzheimer’s disease in patients with mild cognitive impairment was barely more than 50%, and it couldn’t distinguish Alzheimer’s from other forms of dementia.

This highlights how much research is still needed to be able to predict patients’ prognosis. Earlier diagnosis could mean earlier administration of treatments, which might make them more effective in slowing or preventing the onset of Alzheimer’s disease. It would also allow patients and their families more time to plan for the future.

 

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Ketogenic Drug Shows Promise in Early Clinical Trials for Alzheimer’s Disease

There’s a lot of hype surrounding the ketogenic diet, but unlike many other fads, this one may actually have the potential for real benefits. In a study published this week in Experimental Gerontology, researchers tested a recently-developed drug called caprylidene that can simulate the effects of the ketogenic diet.

A small cohort of sixteen Alzheimer’s disease patients was recruited for the study. Fourteen of them were randomly assigned to take caprylidene for 45 days, while the other two took a placebo. The researchers administered brains scans before and after the 45-day period to monitor any changes in the patients’ cerebral blood flow.

They found that most of the subjects who took the caprylidene had higher blood flow in several regions of the brain. This suggests that the drug enhanced the patients’ abilities to metabolize energy in these specific regions. However, the drug seemed to have no effect on patients who possessed the APOE4 allele, a genetic variant that is associated with a greater risk of Alzheimer’s disease.

This small study provides some evidence in favor of the ketogenic diet as a possible treatment for neurodegeneration. As I’ve discussed in one of my previous articles (see Alzheimer’s and Coconut Oil: What does the science say?), the ketogenic diet is based on shifting your body’s primary energy source from carbohydrates to fats. When you deprive your body of glucose, this induces a state of “ketosis,” in which your liver begins breaking down fat stores to form another type of energy-storing molecule called ketones.

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An overview of the ketogenic diet. Image Source

Recently, evidence began to emerge that suggested the ketogenic diet could be useful for people with Alzheimer’s disease. Studies show that the brains of Alzheimer’s patients have a harder time metabolizing glucose, which causes their neurons to be starved for energy. This has led some to suggest that by providing neurons with ketones, the ketogenic diet might allow the brain to access an alternative energy source and perhaps restore some function.

Those of you who have cared for a loved one with Alzheimer’s disease may recognize that implementing a strict dietary plan like the ketogenic diet is next to impossible. This makes drugs like caprylidene, which induces ketosis artificially, a useful alternative.  While the small number of subjects used in this study is cause for caution, it suggests possible merit to this hypothesis and a need to replicate these intriguing findings with a larger sample size.

 

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Herpes Virus Infection May Contribute to Alzheimer’s Disease

A virus with a nearly 100% infection rate could increase the risk of developing Alzheimer’s disease.

The idea that Alzheimer’s disease may be caused in part by microbial infections has been around for decades and recently started to gain increased support with the scientific community. Hundreds of studies have observed an increased incidence of many types of infections in Alzheimer’s disease patients. However, most of these studies could not establish a direct causative link, and they provided little insight into the mechanisms of this interaction.

Recently, a study published in the journal Neuron provided some of the strongest evidence yet for the infectious theory of Alzheimer’s. Researches from the Icahn School of Medicine at Mount Sinai collected portmortem brain samples from people with preclinical Alzheimer’s disease, as well as healthy controls, and used an advanced laser-capture technology to analyze the gene expression in their neurons. They then constructed computational models to predict which patterns of gene expression were associated with Alzheimer’s disease. They noticed that many of these genes that had different expression in the Alzheimer’s brains played a role in immune system’s response to viral infection.

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This figure from the paper illustrates how researchers employed computational models to connect viral infection rates with the signatures of Alzheimer’s disease.

To further investigate this viral connection, the researchers analyzed the levels of viral RNA in each of the brain samples. They found that the Alzheimer’s brains had significantly more RNA from two types of human herpes viruses (HHV): type 6A and type 7. (Note that HHV is not to be confused with human simplex virus [HSV], which is a sexually transmitted infection.) This suggests that people with Alzheimer’s disease have higher rates of HHV infection in their brains.

Furthermore, they found that the viral infections could perturb many genes that are linked to the development of Alzheimer’s disease, including BACE1, which helps create the sticky plaques that are characteristic of the Alzheimer’s brain. HHV-6A also decreases expression of a microRNA gene called miR-155. When they created mice that lacked expression of miR-155, these mice developed Alzheimer’s plaques in their brains, suggesting that this gene could be an important link between herpes infection and Alzheimer’s.

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This figure from the paper shows the complex network of genes that may link herpes virus infection with the development of Alzheimer’s disease.

This study is different from previous ones in several ways. It includes a large sample size from throughout the United States, which provides higher statistical rigor to the conclusions. It also suggests a possible mechanisms by which viral infections could contribute to the development of Alzheimer’s disease via disruption of neuronal gene expression. The results support the intriguing possibility that the toxic amyloid-beta protein, which has long been thought to be the primary cause of Alzheimer’s disease, could actually be a beneficial response to viral infection, a theory that I described in a previous article. While this study is not yet conclusive proof that herpes infection can directly lead to Alzheimer’s disease, it opens that door for many interesting new avenues for research that should be investigated further.

A connection between herpes and Alzheimer’s disease is both troubling and encouraging. HHV types 6 and 7 are extremely common, with nearly 100% of individuals infected by age 3. Most of us are likely infected as infants through the saliva of our parents or other relatives. After the initial infection, the virus becomes latent and remains circulating in the bloodstream for life. For most of us, HHV-6 and HHV-7 infections are completely asymptomatic. However, as we grow older, our immune systems weaken, allowing these viruses to travel from the bloodstream to the brain. Some reports suggest that the resulting neuroinflammation could contribute to common age-related neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.

Yet these results also offer hope. If microbial infections such as HHV are the initial cause of Alzheimer’s disease, this suggests that we could treat the disease using immunosuppressant or antiviral drugs. Should future studies confirm this to be true, this could be a huge boon for the development of effective Alzheimer’s therapies.

 

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Genetic Evidence Suggests Iron is Linked to Alzheimer’s Disease

According to a recent study, people with a rare variant in the HFE gene are three times less likely to develop dementia than the general population.

You’ve probably heard that consuming enough iron is important for overall health. However, too much iron can also be a bad thing. In particular, people with Alzheimer’s disease often have abnormally high levels of iron in their brains. (See The Role of Metals in Alzheimer’s Disease). The question of whether iron is a cause or consequence in Alzheimer’s still remains unanswered.

In a paper published this week in PLoS One, a group of Italian researchers investigated whether the genes that control levels of iron in the body could be related to the risk of dementia. They recruited 765 subjects who had Alzheimer’s disease, vascular dementia, or mild cognitive impairment, as well as 1,086 healthy controls of a similar age. Then they took DNA samples from the subjects and looked at four different genes that are involved in iron metabolism.

They found that one gene called High Ferrum (HFE), which is responsible for controlling absorption of iron from the blood, was protective against dementia. Specifically, subjects who had a particular variant of the HFE gene were one-third as likely to develop Alzheimer’s disease or vascular dementia compared to subjects who didn’t have the protective variant. The effect was even stronger for mild cognitive impairment, which the HFE variant reduced the risk to only one-fifth.

The researchers then looked at another gene called APOE, which has previously been shown to be involved in Alzheimer’s disease. People with the APOE4 variant of this gene were more than four times as likely to have Alzheimer’s. However, in subjects who also possessed the protective HFE variant, the impact of APOE4 was completely attenuated, and their risk of Alzheimer’s was normal.

How could the HFE gene protect people from dementia? One possibility, known as the metal hypothesis of Alzheimer’s disease, suggests that iron makes amyloid-beta plaques more toxic. Amyloid-beta, a protein that accumulates in Alzheimer’s patients’ brains, can interact with various metal ions to become extra toxic. Normally metals are blocked from entering the brain by the blood-brain barrier, but this barrier tends to become leaky in older people. Thus the hypothesis suggests that influx of iron and other metals into the brain may cause amyloid-beta to aggregate and become more toxic, thus contributing to the development of Alzheimer’s.

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The metal hypothesis suggests that the toxicity of beta-amyloid could be increased when it binds to metal ions. Image Source

However, the metal hypothesis can’t entirely explain these recent findings. For one thing, the variants in iron-controlling genes were also protective against vascular dementia, which does not involve amyloid-beta. In addition, the researchers did not observe any differences in blood iron levels based on these genetic variants, so it’s unclear exactly how these genes may be affecting iron metabolism. Future studies are needed to clarify if and how iron could be involved in Alzheimer’s and other types of dementia.

 

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