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.

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.

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.

Report Finds COVID-19 Has Disproportionately Impacted Dementia Patients

A recent report from the International Long-Term Care Policy Network found that the COVID-19 pandemic had a disproportionate negative impact on people living with dementia. The authors collected data from 9 countries: the United Kingdom, Spain, Ireland, Italy, Australia, the United States, India, Kenya and Brazil.

They found that people with dementia accounted for between 29% and 75% of COVID-19 deaths in these countries. Many of these deaths are linked to care homes. Containing the spread of COVID-19 in care homes is very challenging due to the close living conditions, as well as the difficulty of enforcing mask-wearing among residents with dementia.

In order to contain the spread of the virus, many care homes have implemented social distancing measures. However, many of these adjustments could have contributed to worse patient outcomes, as an abrupt change in routine can greatly impair quality of life for dementia patients and lead to physical deterioration.

For example, personal protective equipment (PPE) such as masks, which can cause distress to dementia patients by making it difficult for them to recognize or communicate with their caregivers. In addition, many care homes experienced PPE shortages, causing widespread COVID-19 infections. Furthermore, only half of the care homes surveyed had the proper facilities to isolate a resident who tested positive for COVID-19.

The rapid spread of COVID-19 in care homes led to many staff members testing positive for the virus. As a result, staff shortages were common and residents were often left alone without assistance for long periods of time. One study found that this chronic isolation was an even higher cause of mortality among dementia patients than the virus itself, often due to dehydration.

In addition, many care homes have banned family visits and reduced contact between residents in order to contain the spread of the virus. These measures have caused many patients to experience loneliness, confusion, or depression. Many care homes have not implemented alternative forms of communication, such as video calls or phone calls.

The impact of COVID-19 is not limited to care homes. Studies have found that dementia patients living at home have experienced worse cognitive symptoms, while caregivers report increased stress and burnout. Many sources of support and respite for dementia caregivers are no longer available during the pandemic. In addition, many centers that offer therapies for dementia patients, such as cognitive stimulation therapy or speech and langauge therapy, have closed.

The authors also noted that ageism and ableism have both worsened health outcomes for dementia patients. Ageism is prejudice against people based on their age, while ableism is prejudice against disabled people. Both of these factors compound on each other for dementia patients. As a result, with many ICUs overrun by COVID-19 cases and short on beds and supplies, dementia patients are often denied treatment in favor of younger patients or individuals without a cognitive disability. The lives of dementia patients, and elderly people general, are seen as less valuable by many people, and thus their deaths are downplayed during discussions of the pandemic.

The current situation is certainly harmful for dementia patients and their caregivers. However, the report offered several suggestions for how to keep patients safe from the virus while promoting social interaction. These include increased use of video calling between care home residents and their families, redesigning activities for social distancing (such as hallway bingo), and allowing family visits through glass windows.

They also emphasized that governments must remedy the PPE shortage in order to protect the staff and residents in care homes. Care home staff should also be financially compensated at higher rates due to the huge emotional and physical burden of their position. Finally, the healthcare and elder care systems must be redesigned in order to prevent a future pandemic from having this kind of impact on dementia patients.

For individuals with dementia and their caregivers, here are some helpful resources related to COVID-19:

• Coronavirus (COVID-19): Tips for Dementia Caregivers (Alzheimer’s Association)
• Additional COVID-19 Guidance for Caregivers of People Living with Dementia in Community Settings (Centers for Disease Control and Prevention)
• Information About COVID-19 for Alzheimer’s Disease Patients (Alzheimer’s News Today)

 

[Note to readers: Due to the demands of graduate school, I have not been publishing articles nearly as frequently as I used to. I am planning to resume a more regular publishing schedule moving forward, though I likely will not be as prolific as I was in the past. Thank you for your patience and for sticking with me.]

 

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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.

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.

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.

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.

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.

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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