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There’s a New Drug for Alzheimer’s Disease… But Scientists Aren’t Celebrating.

Unless you’ve been living under a rock for the past week, you’ve probably heard the big news: the FDA has just approved a new drug to treat Alzheimer’s disease, the first new treatment for this condition in nearly 20 years. At first glance, this should be exciting news. Alzheimer’s disease, a neurodegenerative memory loss disorder that affects 1 in 3 people over age 85, has been studied for more than a century with little apparent progress toward a cure. And now, Aducanumab (also called Aduhelm) has been approved! So… why aren’t scientists celebrating?

The Dream of a Cure for Alzheimer’s Disease

To explain the problems with Aducanumab, let’s first back up a bit. This is actually not the first drug that’s been approved by the FDA to treat Alzheimer’s disease. Other drugs like memantine have been on the market for decades. Memantine is designed to temporarily reduce the symptoms of Alzheimer’s disease by targeting NMDA receptors in the brain. Basically, since the neurons in your brain gradually die over the course of Alzheimer’s disease, memantine helps to boost the signaling power of your remaining neurons so that your symptoms are a bit less severe. However, it doesn’t prevent the neurons from dying, so eventually it stops being effective. As a result, memantine is only helpful for mild to moderate stages of Alzheimer’s disease, and it cannot slow the disease’s overall progression or improve the patient’s lifespan. Memantine is like taking a painkiller rather than treating the actual wound.

But Aducanumab is different. In contrast to previous drugs like memantine, Aducanumab is designed to treat the underlying cause of Alzheimer’s disease, not just its symptoms. The hope is that it could actually slow the disease’s progression, giving patients a few more months or even years of life before dementia sets in, or maybe even reversing their symptoms. If successful, this would be a true cure, not just a temporary band-aid.

Aducanumab, like the majority of drug candidates to treat Alzheimer’s disease, was designed based on the amyloid cascade hypothesis, which I’ve covered extensively in other articles. In simple terms, when you have Alzheimer’s disease, a toxic sticky protein called amyloid-beta gradually accumulates in your brain, becoming more widespread over time. The amyloid cascade hypothesis says that by reducing levels of amyloid-beta, we could slow or halt the disease’s progression.

And this makes sense: if you saw a patient whose brain was full of a toxic protein, you’d probably assume that getting rid of the protein would be the key to treating the disease. But after decades of research and hundreds of failed clinical trials, concrete evidence in favor of the amyloid cascade hypothesis has never materialized. Drugs have been invented that effectively reduce amyloid-beta in the brain, yet the patients showed minimal improvement in their symptoms, and some even got worse. Other studies have shown that many people can develop high levels of amyloid-beta in their brains without ever experiencing symptoms of Alzheimer’s disease.

After years of failed research, much of the neuroscientific community has moved on from the amyloid cascade hypothesis in favor of a more nuanced understanding of this disease. Maybe targeting another toxic protein called tau, which also accumulates in Alzheimer’s patients’ brains, will be more effective. Maybe amyloid-beta is an immune response and it’s actually brain infections that are to blame. Maybe accumulating metal ions are to blame. There are many new theories to explain the cause of Alzheimer’s disease, and it’s likely that all of them are correct to some degree, each contributing a small component of an individual’s overall risk for the disease. One thing, at least, seems clear: amyloid-beta alone is not enough to cause or to cure Alzheimer’s disease.

How Did We Get Here? The Story of Aducanumab

But let’s get back to Aducanumab. This drug is what’s called a monoclonal antibody. Essentially, it’s a small protein that’s designed to bind to amyloid-beta aggregates and help clear them out of the brain. To test this drug, Biogen (the company that makes Aducanumab) recruited nearly 2000 patients into two different phase 3 clinical trials, where they would receive either the drug or a placebo. After a three-month treatment period, the patients took a variety of cognitive tests to assess their dementia symptoms.

In March 2019, Biogen announced that they were suspending their Aducanumab clinical trials, stating that the drug did not show evidence of efficacy in treating the cognitive symptoms of Alzheimer’s disease. For a while, it seemed like that was that. Just another failed clinical trial for Alzheimer’s disease, as hundreds had failed before.

However, in October 2019, Biogen released another statement. They had repeated their analysis with an additional ~300 patients who were not included in the original calculations, and found that there was a detectable improvement in cognitive scores resulting from the treatment. That improvement was marginal, around 20%, though it did reach statistical significance. They applied for FDA approval through the accelerated pathway, which is the same pathway that was used to rapidly approve the COVID-19 vaccines. This pathway is designed to allow urgently-needed, potentially life-saving treatments to progress more quickly through the standard FDA approval pipeline, with the caveat that the companies must conduct additional studies in the future to confirm their efficacy.

The accelerated pathway made sense for the COVID-19 vaccines, which showed very high efficacy and mild side effects in clinical trials. In contrast, Aducanumab came with miniscule improvements in cognitive symptoms and a risk of severe side effects, including bleeding inside the brain, falling, and confusion/delirium. The drug did seem to be effective at reducing amyloid-beta levels, but as I explained above, this often does not correlate with any meaningful improvements for the patients. Perhaps unsurprisingly, when the FDA advisory committee reviewed the evidence in November 2020, they voted unanimously to reject Aducanumab for FDA approval.

While the advisory committee’s decisions are technically just a recommendation, the FDA almost always makes the final decision in line with their ruling. But in this case, the FDA went against the committee’s decision and approved Aducanumab via the accelerated pathway. This will allow Biogen to being selling the drug to patients almost immediately. They are required to conduct an additional trial with stronger evidence that the drug is effective, but these results are not due until 9 years from now, giving Biogen plenty of time to draw a profit in the meantime.

Though the FDA states that this decision was based on the evidence, it seems likely that external pressures played a role as well. The Alzheimer’s Association and the American Geriatrics Society both issued letters to the FDA urging them to approve the drug. Now, as someone who has been actively involved with the Alzheimer’s Association for years, I truly believe that both of these organizations acted in good faith. Alzheimer’s is such a devastating disease, and the past decades of failed research have been incredibly frustrating. I can understand why they would want to pursue that small glimmer of hope. But I’m concerned that the evidence is simply not on their side in this case.

The Enormous Costs of Aducanumab

Now you may be asking: so what? Maybe the drug isn’t that effective, maybe it’s not even effective at all. But what’s the harm? Shouldn’t we at least try it out and see if it helps people?

Even if we ignore the potential side effects, the financial implications of Aducanumab are set to be staggering. The drug is expected to cost each patient an average of $56,000 per year. Most of this cost will be shouldered by the taxpayers.

How much will this cost us? According to a recent article in The Atlantic, if we assume that only one-third of the six million Americans living with Alzheimer’s disease choose to take the drug, that adds up to $112 billion in annual healthcare spending. That’s more than Medicare spent on all prescription drugs combined during 2020! This drug has the potential to put extreme pressure on the Medicare and Medicaid systems, not to mention the remaining out-of-pocket costs that Alzheimer’s patients and their families will struggle to pay.

Now, if this drug were actually effective, I would argue that these financial costs would be well worth it, both for the improvements in patients’ quality of life and for the concrete fiscal benefits of reduced spending on long-term care facilities. But to take on such a financial burden for a drug whose benefit seems marginal at best… to be honest, I’m very worried. Furthermore, this drug sets a dangerous precedent for other pharmaceutical companies. What other drugs may be forced through the FDA approval pipeline based on shaky evidence and powerful lobbying?

Many other scientists and physicians have voiced their concern over Aducanumab. Dr. Jason Karlawish, a practicing physician and medical faculty at U Penn, wrote that he will not prescribe the drug to any of his patients. Dr. Robert Howard, a professor of old age psychiatry at University College London, stated, “Now, we’ll wait a decade before it becomes obvious to everyone that there are no benefits – only high healthcare costs –- associated with the treatment.” Even Dr. Derek Lowe, a well-known drug discovery researcher in the pharmaceutical industry, has cast his vote against the drug.

Conclusion: Where Do We Go From Here?

With all that said, here we are. Aducanumab is approved, and patients will start receiving the drug soon. Biogen has nearly a decade before they have to prove the treatment is really effective. Only time can tell how this will impact our healthcare system. I am worried that the FDA has gone over the heads of its own advisory committee, in the face of strong evidence against the amyloid cascade hypothesis, and made a decision that will have huge health and financial implications for years to come.

It’s a gloomy picture I’m painting here, but while I don’t personally have much faith in Aducanumab, I haven’t given up on the dream of curing Alzheimer’s disease. There are still many promising new avenues to explore for treating this condition and understanding its true cause. Broadly speaking, I’m optimistic about the future, and I hope that the implications of Aducanumab will not set us back too far.

Before I wrap this up, I want to make one thing clear to those of you who are living with Alzheimer’s or are close with someone who is. I am not saying that you, as an individual, should not take this drug. I’m also not saying that you should take it. That is a decision between you and your physician. Maybe this drug will turn out to be amazing, or maybe it will be a flop. In the meantime, we need to all make the best decisions we can based on the available evidence and our personal values.

New Type of Brain Immune Cell Implicated in Alzheimer’s Disease

When most people think of the brain, we primarily imagine neurons. Neurons are the cells that use electrochemical signaling to directly control our thoughts, actions, and memories. However, neurons are not the only type of cell in the brain. Microglia are a type of immune cell that protects the brain against infections or injuries, among other important roles. One particularly important function of microglia is that they help to clear away amyloid-beta, a toxic protein that is believed to cause Alzheimer’s disease when it accumulates in the brain.

A group of researchers from the University of Pennsylvania wanted to learn more about the role microglia play in Alzheimer’s disease. Their work was published in the journal Acta Neuropathologica.

The researchers used a fairly new technique called single-nuclei RNA sequencing (snRNA-seq), which can reveal what genes are expressed in individual cells. They analyzed cells from the brains of deceased human Alzheimer’s disease patients. By analyzing their gene expression, they were able to categorize the microglia into four distinct groups. One of these groups, called amyloid-responsive microglia, may be important for avoiding Alzheimer’s disease by keeping toxic amyloid-beta at bay.

Next, the researchers wanted to focus on two particular genes called APOE and TREM2. Both of these genes may be involved in regulating how microglia respond to amyloid-beta. Previous studies have shown that genetic variants in APOE and TREM2 can influence the risk of developing Alzheimer’s disease.

The researchers looked at the brains of people who had versions of APOE and TREM2 that are associated with a higher risk of Alzheimer’s disease. These versions are known as risk variants. They found that individuals with risk variants in these two genes had fewer numbers of amyloid-responsive microglia in their brains. This result is exciting, as it provides a potential mechanism for how these genes influence the risk of Alzheimer’s via changing a particular category of microglia.

“These findings demonstrate that not all microglia respond the same to protein that builds up, or aggregates, in the brain,” says Dr. Aivi Nguyen, a former neuropathology and post-doctoral fellow who was the lead author on the paper. “Moreover, certain genetic risk factors are associated with specific types of microglial responses. Thus, neuroinflammation, or microglia getting revved up, may not be as binary as “good” or “bad.” Perhaps the answer is simply: it depends.”

Dr. Nguyen says she first became interested in this topic due to having a family member with Parkinson’s disease. “I did not realize how much I would enjoy the field, though,” she added. She also commented on the importance of a positive lab culture for her scientific success. “I have found this community to be incredibly supportive and encouraging, particularly as a woman neuropathologist.  An example of this positive culture is my mentor, Dr. Eddie Lee, who has helped me enormously and has advocated on my behalf on countless occasions.”

Dr. Nguyen and her coauthors plan to follow up on this study by investigating amyloid-responsive microglia in more detail. Their research could offer new insights into the role microglia play in Alzheimer’s disease and whether they could be a target for future therapeutics.

Education promotes cognitive reserve against dementia… but only if you’re white.

A headshot of a young woman smiling at the camera. She has brown hair and is wearing a black and white striped shirt.

Guest author: Justina Avila-Rieger, PhD is a postdoctoral fellow of Neuropsychology in Neurology at the Gertrude H. Sergievsky Center and the Taub Institute for Research in Aging and Alzheimer’s disease at Columbia University. She completed her graduate training in clinical psychology, with an emphasis on neuropsychology and quantitative methodology, at the University of New Mexico and completed her clinical internship at the Baltimore VAMC. Her research examines racial/ethnic and sex/gender disparities in Alzheimer’s disease.

Experts have long suggested that keeping your brain active, especially through continued education, is a great way to protect our brains against dementia as we age. The idea is that education allows our brain to build up a “cognitive reserve,” which acts as a buffer to slow the onset of dementia. However, our recent paper found that this advice may only apply to White people.

Cognitive reserve is the ability to maintain thinking abilities even if the brain is damaged. Many brain functions are flexible and can compensate or change to make added resources available to cope with challenges. The term cognitive reserve is used to describe this disconnect, when cognitive function is not as impaired as would be expected given the level of brain degeneration.1 In other words, for people with a high level of cognitive reserve, their brains can show severe signs of degeneration, yet their dementia symptoms are much milder than would be expected.

A chart with AD neuropathology on the x-axis and cognitive status on hte y-axis. A green line, indicating a person with high cognitive reserve, has higher cognitive status even in the presence of neuropathology. A yellow line, indicating a person with low cognitive reserve, has lower cognitive status with the same level of neuropathology. A horizontal red line indicates incident dementia, showing that the person with higher cognitive reserve does not develop dementia until their neuropathology is much more severe than the person with low cognitive reserve.
This figure illustrates the idea of cognitive reserve. People with high cognitive reserve can have severe Alzheimer’s disease (AD) neuropathology, yet not experience any cognitive symptoms. Image source

Some indicators of life experiences and contexts, including years of education, are often used as proxies for cognitive reserve because they are associated with lower dementia risk and delayed age of dementia onset.2 However, the majority of cognitive reserve studies have been conducted in predominantly non-Latinx White (White) samples and do not consider racial or ethnic differences in educational experiences. (Note: Latinx is the gender-neutral form of Latino/Latina and refers to people originating from Latin America.)

In our recent study, we tracked a community of 1,553 White, Black, and Caribbean-born Latinx  older adults over time.3 We found that White individuals with more years of education had slower cognitive decline compared with White individuals with fewer years of education, despite having the same level of brain degeneration. In other words, greater years of education buffered the effects of brain degeneration for White people. However, for Black and Latinx individuals, years of education did not protect cognitive function against the effects of brain degeneration.

Why might the protective effects of education differ across racial/ethnic groups? My colleagues and I suggest that racism is likely to be the primary underlying reason that having more years of school contributed to cognitive reserve in Whites, but not among Black or Latinx participants. Most Black older adults in the United States were born and raised in the South,4 where Jim Crow laws enforced segregation and limited opportunities within education, health care, housing, and the labor market.5 Across all U.S. states, both before and after Brown v. Board of Education, racist policies and residential segregation forced Black children to attend underfunded schools that had large student/teacher ratios, shorter term length, lower teacher salaries, and inadequate budgets for supplies and school buildings.6 These structural inequalities contribute to lower returns from education among Blacks compared to Whites.7

Similarly, older Caribbean-born Latinx who grew up outside of the United States also had fewer opportunities to attend school and/or received a poor quality of education.8,9 Years of education may not adequately represent the effect of life-course experiences that contribute to cognitive reserve across all racial/ethnic groups. As a result, the contribution of years of education to cognitive reserve is reduced for racial/ethnic minorities.

Even if educational experiences were equivalent across groups, structural racism impacts adult opportunities that might contribute to cognitive reserve across racial/ethnic groups. Racism in the labor market has served to counteract the benefits of schooling for Black Americans. For example, Black men continue to have lower employment rates than White men even if they have the same educational attainment10. It is also possible that the protective effects of education are reduced by stress associated with institutional racism and discrimination.

Do these findings mean that Black and Latinx individuals do not have cognitive reserve? Absolutely not. Rather, these findings suggest that years of education is just not a good indicator of the life-course experiences that contribute to cognitive reserve in Black and Latinx people. Several studies have demonstrated that measures of school quality may be a better indicator of educational experiences in racial/ethnic minorities than years of education.7–9,11,12 There is also evidence that early life educational policies13 influence later life dementia risk and cognitive decline, above and beyond educational attainment. There are also other early life experiences14 (e.g., childhood socioeconomic status, neighborhood factors) that may better indicators of cognitive reserve among Blacks and Latinx.

Overall, our findings provide more evidence that social inequalities across the lifecourse have an impact on racial and ethnic disparities in Alzheimer’s disease. Inequalities in school opportunities, including school segregation and limited governmental investment in schools that served Black and Latinx children, as well as racial discrimination in occupation, housing, criminal justice, and healthcare can help to explain why there are diminished “brain health” returns to educational attainment for Black and Latinx older adults. Considering that Black and Latinx individuals are 2 to 3 times more likely to develop Alzheimer’s disease than White individuals,15 more research is needed to understand the life-course factors that contribute to cognitive reserve. Such work may lead to identification of factors that may narrow racial/ethnic inequalities in the onset and progression of Alzheimer’s disease.

Sources:

  1. Mungas D, Gavett B, Fletcher E, Farias ST, DeCarli C, Reed B. Education amplifies brain atrophy effect on cognitive decline: Implications for cognitive reserve. Neurobiol Aging. 2018;68:142-150. doi:10.1016/j.neurobiolaging.2018.04.002
  2. Amieva H, Mokri H, Le Goff M, et al. Compensatory mechanisms in higher-educated subjects with Alzheimer’s disease: a study of 20 years of cognitive decline. Brain J Neurol. 2014;137(Pt 4):1167-1175. doi:10.1093/brain/awu035
  3. Avila JF, Arce Renteria M, Jones RN, et al. Education differentially contributes to cognitive reserve across racial/ethnic groups. Alzheimers Dement.
  4. Ruggles S, Sobek M, Alexander T. Integrated Public Use Microdata Series: Version 3.0. Minnesota Population Center; 2004.
  5. Barnes LL, Bennett DA. Alzheimer’s disease in African Americans: Risk factors and challenges for the future. Health Aff. 2014;33(4):580-586.
  6. Hedges LV, Laine RD, Greenwald R. Does Money Matter? A Meta-Analysis of Studies of the Effects of Differential School Inputs on Student Outcomes. Educ Res. 1994;23(3):5-14. doi:10.3102/0013189X023003005
  7. Manly JJ, Jacobs DM, Touradji P, Small SA, Stern Y. Reading level attenuates differences in neuropsychological test performance between African American and White elders. J Int Neupsychological Soc. 2002;8:341-348.
  8. Sisco S, Gross AL, Shih RA, et al. The role of early-life educational quality and literacy in explaining racial disparities in cognition in late life. J Gerontol B Psychol Sci Soc Sci. 2013;70(4):557-567.
  9. Manly JJ, Jacobs DM, Sano M, et al. Effect of literacy on neuropsychological test performance in nondemented, education-matched elders. J Int Neupsychological Soc. 1999;5:191-202.
  10. McDaniel A, DiPrete TA, Buchmann C, Shwed U. The black gender gap in educational attainment: historical trends and racial comparisons. Demography. 2011;48(3):889-914. doi:10.1007/s13524-011-0037-0
  11. Manly JJ, Byrd D, Touradji P, Sanchez D, Stern Y. Literacy and cognitive change among ethnically diverse elders. Int J Psychol. 2004;39(1):47-60.
  12. Arce Renteria M, Vonk JMJ, Felix G, et al. Illiteracy, dementia risk, and cognitive trajectories among older adults with low education. Neurology. 2019;93(24):2247-2256.
  13. Dementia risk likely measurable among adolescents, young adults. Accessed August 27, 2020. https://www.healio.com/news/psychiatry/20200730/dementia-risk-likely-measurable-among-adolescents-young-adults
  14. Xu H, Yang R, Qi X, et al. Association of Lifespan Cognitive Reserve Indicator With Dementia Risk in the Presence of Brain Pathologies. JAMA Neurol. Published online July 14, 2019. doi:10.1001/jamaneurol.2019.2455
  15. Facts and Figures. Alzheimer’s Disease and Dementia. Accessed August 27, 2020. https://www.alz.org/alzheimers-dementia/facts-figures

Note: This post was originally titled “Education protects against dementia… but only if you’re white.” This is inaccurate, and the title has been corrected accordingly.

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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Ultrasound and Microbubbles May Be Used to Treat Alzheimer’s Disease

Alzheimer’s disease, the most common form of dementia, is characterized by the buildup of toxic, sticky plaques inside the brain. These plaques are made of a protein called amyloid-beta. Although hundreds of drug candidates that try to remove amyloid-beta from the brain have been tested in clinical trials, these have been a resounding failure (see “Where’s our cure to Alzheimer’s disease?”). This has led scientists to try out new methods for treating the disease.

One of the most intriguing ideas for treating Alzheimer’s is to use ultrasound. Ultrasound uses high-frequency sound waves outside the range of human hearing. These sound waves can pass through soft tissues but bounce off of denser things such as bone, which is how ultrasound can generate the image of a fetus during pregnancy.

Ultrasound has many uses outside of imaging. One recent techniques involves injecting the patient with tiny “microbubbles.” When hit with an ultrasound pulse, the microbubbles expand and contract. This allows them to gently press against the blood vessel walls without damaging them.

The microbubble ultrasound technique has an interesting effect inside the blood-brain barrier (BBB). The BBB is a complex structure that surrounds blood vessels inside the brain. It prevents harmful toxins and pathogens from entering the brain, but can also make it difficult for waste products (including amyloid-beta) to be cleared away.

blood-brain-barrier_med.jpeg

The cells surrounding blood vessels in the brain, known as the blood-brain barrier, prevent large molecules from passing through. Image Source

When microbubbles inside the brain’s blood vessels expand, they can temporarily open the BBB. This not only allows for enhanced clearance of waste products, but also activates many immune pathway in the brain that further assist with this process.

Early experiments involving mice have been encouraging. In 2013, 2014, and 2015, three different research groups found that mice that were genetically engineered to develop Alzheimer’s disease showed improvements after ultrasound/microbubble treatments. This included reduced levels of amyloid-beta, improved spatial memory, and more newborn neurons inside the hippocampus, a part of the brain associated with memory.

Several human trials involving ultrasound are currently being planned or in progress. One small trial of five subjects found that the ultrasound device could safely and reversibly open the BBB. However, we still need to wait for more results to come out before we’ll know whether this strategy is effective for treating Alzheimer’s.

It also remains to be seen whether ultrasound may come with any unforeseen consequences. It’s possible that opening the BBB could allow certain immune cells or pathogens to enter the brain, creating an opportunity for autoimmune reactions or brain infections. Despite the potential risks, researchers remain hopeful that ultrasound could offer a noninvasive means for treating Alzheimer’s disease in the future.

 

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Why Are Women Twice as Likely to Get Alzheimer’s Disease?

Of the more than 5 million Americans living with Alzheimer’s disease, nearly 2/3 of them are women. A woman in her 60s has a 1 in 6 chance of later developing Alzheimer’s, compared to only 1 in 11 for a man. What is the cause for this sex imbalance?

A major player in this question is the APOE gene (see The Genetics of Alzheimer’s Disease for more detail). This gene comes in three different forms: APOE2, APOE3, and APOE4. Each of us inherits two copies of this gene (one from each parent). If you have one copy of APOE4, your risk of Alzheimer’s increases threefold, while having two copies of APOE4 increases your risk by fifteen times. For reasons that remain unclear, the APOE4 allele seems to be a stronger risk factor for women than men, which could help to explain the difference in Alzheimer’s prevalence.

Some lines of research suggest that sex hormones may also play a role. Specifically, reduced estrogen levels, which commonly occur during menopause, are associated with increased risk of Alzheimer’s. Several studies have shown that women with Alzheimer’s tend to have lower estrogen levels in their brains. Pregnancy also reduces lifetime exposure to estrogen, which may explain why women who have had biological children have a higher risk of dementia than women without biological children. Similarly, women who have had a hysterectomy or oophorectomy (removal of the uterus or ovaries), which can induce menopause at an earlier age, also have an increased risk of dementia.

menopause-s2-chart

A woman’s estrogen levels decrease as they approach menopause, which may be linked to their increased risk for Alzheimer’s. Image Source

So if low estrogen is a risk factor for Alzheimer’s, could estrogen replacement therapy (ERT) combat this? ERT is commonly used as a treatment for menopausal symptoms such as hot flashes, as well as to reduce the risk of osteoperosis. Clinical trials investigating the effects of ERT on dementia have had mixed results. There is some evidence to suggest that it may only be protective if women begin treatment within the first few years of menopause. So far, the jury is still out on whether these therapies could be beneficial for preventing dementia. There are also some notable risks associated with ERT, including a higher chance of breast cancer.

What about male sex hormones? Similarly to women, men with Alzheimer’s disease tend to have lower levels of testosterone than normal. So if the loss of both sex hormones can increase the risk of Alzheimer’s, why do we see a much higher prevalence in women? One theory is that it relates to how quickly these hormones are lost. The menopause transition usually takes around four years, while male reproductive aging takes place gradually over several decades. Perhaps the abruptness of estrogen loss in menopause is responsible for the higher risk of dementia.

Another important difference between men and women lies in their risk for other dementia-related diseases. Women are more than twice as likely as men to have depression, and they also have a higher risk of insomnia and fragmented sleep. All of these conditions are linked to an increased risk of Alzheimer’s. In addition, women have historically been granted less access to education, employment, and physical exercise, which can be protective against dementia. This is particularly true for women who grew up in the mid-20th century and are now reaching their elderly years.

In conclusion, there’s still a lot we have to learn about why women are more prone to Alzheimer’s disease than men. In the meantime, both women and men can still greatly reduce their overall risk of Alzheimer’s through lifestyle changes. See 10 Tips to Reduce Your Dementia Risk to learn more.

 

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Why People with Down Syndrome are at High Risk for Alzheimer’s Disease

Down syndrome is a neurodevelopmental disorder caused by inheriting an extra copy of chromosome 21. The most common symptoms include intellectual disability, unusual facial features, and heart defects. About 1 in 700 babies is born with this condition.

The average lifespan for a person with Down syndrome is 60 years. Sadly, the last few years of their lives are often lost to Alzheimer’s disease. Nearly two-thirds of Down syndrome patients are diagnosed with Alzheimer’s before the age of 60. This is far higher than the general population, of whom less than 1% develop Alzheimer’s this early in life.

The reason for this greatly elevated risk of Alzheimer’s disease comes down to genetics. While chromosome 21 contains hundreds of different genes, a single gene is believed to cause Alzheimer’s disease in Down syndrome patients: APP. This gene encodes a protein called amyloid-beta. Amyloid-beta is a toxic, sticky protein that can clump together and accumulate inside the brain, which is believed to be a major contributing factor to Alzheimer’s disease.

Because of their extra copy of chromosome 21, people with Down syndrome produce more amyloid-beta than normal. Nearly 100% of Down syndrome patients start to develop amyloid-beta aggregates in their brains during their 40s. This puts them at a very high risk of developing Alzheimer’s at an early age.

After the practice of institutionalizing people with Down syndrome became less common, their life expectancy improved dramatically, up from only 25 in 1983 to 60 today. However, this means that more Down syndrome patients are living long enough to develop Alzheimer’s disease, which is a frightening prospect to these individuals and their families.

Despite the troubling statistics, there is hope for people with Down syndrome. Many neuroscientists believe that early intervention is key for preventing Alzheimer’s disease. However, ethical standards make it difficult to administer treatments to people before we know for sure that they’ll develop a disease, particularly if those treatments come with certain risks. This makes it challenging to test out new preventative therapies for Alzheimer’s disease.

Because of the very high rate of Alzheimer’s disease among Down syndrome patients, they may be an exception to this rule. New drug candidates can be tested on these individuals beginning early in life, which may prove to be a more effective strategy for preventing Alzheimer’s. While only time can tell whether these treatments will prove beneficial, many remain hopeful for the future of research.

 

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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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Interview with a Dementia Researcher: Rory Boyle, Cognitive Neuroscience Researcher

What areas of research are you currently pursuing?

My PhD research is focused on using machine learning to identify markers of cognitive ageing. Currently, I am working on a project which uses machine learning and MRI scans to create a model of normal or healthy brain ageing. This model can be used to estimate how well, or poorly, a person’s brain is ageing and this estimation is termed the brain-predicted age difference, or brainPAD.

It has already been shown that people who have high brainPAD scores (which means their brains are ‘older’ relative to their actual age) have a higher risk of early mortality and tend to perform worse on measures of physical functioning (such as grip strength, lung function, walking speed).

However, we don’t yet know whether brainPAD can be used as a measure of cognitive ageing. If people with high brainPAD scores are shown to perform worse on tests of cognitive function, then brainPAD could potentially be used as a way of identifying such people at a very early stage, before cognitive decline is noticed using standard cognitive tests.

The next project in my PhD will look at developing an objective measure of cognitive reserve. Some people whose brains have the hallmarks of Alzheimer’s disease or other dementias seem to be able to maintain normal cognitive function. This has led researchers to try and understand why some people might have a buffer or some form of protection against certain neurodegenerative diseases. One theory is that people who are able to tolerate such neurodegeneration have high levels of what is called ‘cognitive reserve’.

Cognitive reserve refers to an individual’s ability to use their brain irrespective of their brains’ structural health. It is proposed that life experiences, such as education, occupational attainment, engagement in social, leisure, and mentally stimulating activities, and physical activity contribute to cognitive reserve.

However, currently, cognitive reserve is typically measured by questionnaires and interviews which measure these same factors (education, occupational attainment, etc.). This means that we might not have the most accurate measures, as people might not fully remember all the details of their education or social activities and their answers might be affected by response bias!

My goal is to use neuroimaging to develop an objective and standardised measure of cognitive reserve so that people with low cognitive reserve can be identified. This would allow for interventions to be directed at these people and it would also help in studies evaluating strategies to improve cognitive reserve.

What are the big questions or theories currently being debated in your subfield?

There are a couple of big questions which people are trying to answer in relation to cognitive reserve. Can cognitive reserve be objectively measured, and if so, how? What is the neural basis of cognitive reserve? Hopefully my project will help to shed some light on these questions.

What is a common misconception related to dementia that you often encounter?

One common misconception is that there nothing we can do to reduce our risk of dementia. Given our knowledge of cognitive reserve, one way we could reduce our risk of dementia is by increasing cognitive reserve! There is more and more evidence that taking part in mentally stimulating activities, being socially active, and regularly exercising can lower the risk of dementia. More generally, there is evidence that having a healthy diet, particularly a Mediterranean diet, not smoking, and cutting down on alcohol can also reduce the risk of dementia.

What recommendations would you give to people wanting to reduce their risk of Alzheimer’s disease?

Like a lot of things, the best recommendations for reducing risk of Alzheimer’s disease or other dementias are to live a healthy and active life. Specifically, try to exercise three times a week, particularly aerobic exercise like brisk walking, swimming, cycling. As well as that, try to stick to a Mediterranean diet, which is rich in fruits and vegetables, whole grains, beans and nuts, olive oil and fish.

Be socially active, join a group or club. In Ireland, we have a really great initiative called Men’s Sheds were men can meet up and work together on hobbies and meaningful projects. This is a great example of how people can keep socially engaged. As well as that, take part in mentally stimulating activities like puzzles and Sudoku. If you have access to a PC, there are now thousands of free online courses on websites like Coursera or EdX. By signing up for these, you can challenge yourself and learn something new, all while keeping your brain stimulated!

How can non-scientists contribute to the fight against Alzheimer’s?

Non-scientists could help in the fight against Alzheimer’s by taking part in research. Research studies are always on the lookout for participants. People without Alzheimer’s disease are always needed as well to form control groups. Have a look online or at any nearby universities!

On top of that, there are now even easier ways to take part in research. For example, downloading and playing the SeaHero Quest app allows researchers to collect valuable information about how the brain navigates in space, which is a key skill that declines early on in dementia.

When do you believe a viable Alzheimer’s treatment will be available?

I’m not sure, but I am hopeful that with all of the new techniques we will be able to identify people likely to develop Alzheimer’s or other dementias, earlier than ever before. This will allow for any interventions that can help with Alzheimer’s to be implemented at the early stages of the disease, where interventions are likely to be most specific. It will also help researchers test and monitor the effects of new interventions and treatments.

Is there any other information you’d like to add?

My PhD research is funded by the Irish Research Council, in partnership with Altoida AG. I am very grateful for the support of both of these organisations. Altoida AG has developed an app that uses computerised and gamefied tests of cognitive performance to evaluate perceptual and memory function in older adults. This app may ultimately allow for early screening of mild cognitive impairment and identification of people who are at risk of developing Alzheimer’s disease. We have tested this app on a number of older adults here in Trinity College, and hopefully we will have some interesting data from these tests in the next year!

 

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Rory Boyle is a PhD candidate in the Whelan Lab in Trinity College Dublin. He graduated with a BSc in Psychology from Dublin City University in 2014, and an MSc in Brain Sciences from the University of Glasgow in 2016. His BSc research project compared the effects of aerobic exercise and caffeine consumption on measures of mood and cognitive performance. His MSc research project used EEG to investigate the age-related differences in the visual processing of faces. Specifically, his project examined whether there were differences in the information content of brain activity during the visual processing of faces.

 

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Interview with a Dementia Researcher: Dr. Aida Suarez Gonzalez, Clinical Neuropsychologist

What areas of research are you currently pursuing?

I am a clinical neuroscientist with a strong translational focus. I have a passion for non-pharmacological interventions and evidence-based services to help people to live well with dementia.

What are the big questions or theories currently being debated in your field?

The development of new multicomponent functional interventions in dementia (such as disease education, counselling, goal-setting, goal-oriented cognitive rehabilitation, coping strategies training, etc.) is a hot topic. These interventions have the potential to increase autonomy, quality of life, and mental health in patients and families.

Another big concept is the need to develop more suitable methods to produce high quality evidence in support of non-pharmacological interventions. The traditional methods used in classic drug trials do not always makes sense when applied to non-pharmacological approaches.

I am also interested in the introduction of a new generation of purpose-built assistive technologies (such as specific communication aids, adapted e-readers, memory aids, etc.). These tools are revolutionizing the way we provide support, so people can remain independent for longer. IDEAL and GREAT are two examples of programs that support the concept of living well with dementia.

What is a common misconception related to dementia that you often encounter?

There are two big misunderstandings that particularly trouble me because they produce undesirable consequences when a diagnosis of dementia is provided.

First, we always highlight that dementia is not a natural part of aging, that it is a disease. However, we usually forget to add that this is a very common disease in old age and that we, as longer-living societies, have lived with age-related diseases for centuries (and hey, here we are after all).

I don’t mean we should belittle the seriousness of dementia, but rather encourage more acceptance and reconciliation with life and trust in the resilience of what we human beings are capable of. I think this way of thinking moves the focus from the frustration of the current absence of a treatment to reflecting on what we can do to live well with the disease. And of course this way of seeing things is not incompatible with increasing research efforts towards finding a cure.

Secondly, calling the dementias “dementias” contributes the stigma and misunderstanding of the disease. In many societies across the world, the word dementia means losing yourself, your reasoning, judgement, understanding and contact with reality. And this is not true. This is a false and unfair misconception that every day strips millions of people around the world from their social roles and right to decide about their lives, and exposes them to patronization.

Of course, advanced stages of the disease do impair your thinking skills severely, but this is not the case in the early and even moderate stages (that can last for many years) and it also depends a lot on the dementia subtype that you have. With the right support, many people with progressive cognitive impairment can lead fairly independent lives for a long time.

Look for example at the UK Network of Dementia Voices, which is a community of 100 groups of people living with dementia that seeks to magnify their own views, make their voices being heard and pressure the public administration to include their advice in matters that affect them.

The same applies to the 3 Nations Dementia Working Group, who are a powerful group of people living with dementia transforming the way we perceive dementia and progressive cognitive impairment by making an extraordinary contribution to society through education and raising awareness. They do public speaking, provide input to public policy bodies and bring value, advice and information about what is like the experience of living with dementia. They have dementiayes, and also they are inspiring, powerful and they are transforming the world.

What recommendations would you give to people wanting to reduce their risk of Alzheimer’s disease?

There is quite a lot of scientific consensus around the main preventive measures: healthy diet, good control of vascular risk factors such as cholesterol, diabetes and hypertension, regular physical exercise, remaining mentally active, and maintaining strong and good quality social bonds and social networks.

How can non-scientists contribute to the fight against Alzheimer’s?

The lay public can make a powerful contribution by trying to educate themselves about dementia, understanding better the changes experienced by a person with the disease, and committing to contribute towards a more dementia-friendly society.

For example, if you run a fruit shop in a neighborhood with an aged population, it’s very likely that some of your clients may be living with memory problems. You can seek information to educate yourself to understand better what that means and place a sign in your shop window explaining that this is a “memory problems friendly shop” and that people can come and speak to you about how to better support them to continue doing their shopping safely and independently.

When do you believe a viable Alzheimer’s treatment will be available?

I wish I had a response for that and I wish that response was “soon.” However, it is possible that we still have to live with Alzheimer’s in our lives for a long time, so I would encourage researchers and policy-makers to double efforts on finding a treatment, but also on helping us having good, purposeful, meaningful and fulfilling lives even if carrying a diagnosis of Alzheimer’s. There is a lot of life beyond the diagnosis, let’s also embrace that and make the best of it.

Is there any other information you’d like to add?

I would like to encourage other scientists to join a movement for change that focuses more on people and less on the disease, at least in the case of the diseases for which a cure has not been found yet. We hardly have any relevant tools to use in clinical studies to measure the impact of non-pharmacological interventions on people’s real lives and this needs to change. Current methods in this area are so quantitatively constrained and disease-oriented that allow little flexibility and, their resulting scientific outputs are usually difficult to translate into clinically practice.

 

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Dr. Aida Suarez Gonzalez is a clinical neuropsychologist at University College London’s Dementia Research Centre. She earned her Masters degrees in Gerontology and Clinical Neuropsychology, as well as her PhD in Neuropsychology, from the University of Salmanca in Spain.

 

 

 

 

 

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