Could Cholesterol Help Drive Alzheimer’s Disease?

Cholesterol made in the brain may spur development of Alzheimer’s disease, a new study suggests.

Cholesterol made by cells called astrocytes is needed for controlling production of amyloid beta, a sticky protein that builds up in the brain and accumulates into the plaques that are the tell-tale sign of Alzheimer’s.

Researchers say these new findings may offer insight into how and why plaques form and may help explain why genes tied with cholesterol have been linked to increased Alzheimer’s risk.

“This study helps us to understand why genes linked to cholesterol are so important to the development of Alzheimer’s disease,” said study co-author Dr. Heather Ferris, an assistant professor at the University of Virginia School of Medicine.

“Our data point to the importance of focusing on the production of cholesterol in astrocytes and the transport to neurons as a way to reduce amyloid beta and prevent plaques from ever being formed,” she said in a university news release.

Researchers found that astrocytes contribute to Alzheimer’s progression by making cholesterol and sending it to neurons. This cholesterol buildup increases amyloid beta production and, in turn, fuels plaque accumulation, according to the authors.

They found that blocking cholesterol production decreases amyloid beta production in mice. It’s too soon to say if this could happen in people and prevent plaque formation, they said.

“If we can find strategies to prevent astrocytes from over-producing cholesterol, we might make a real impact on the development of Alzheimer’s disease,” Ferris said.

“Once people start having memory problems from Alzheimer’s disease, countless neurons have already died,” she added. “We hope that targeting cholesterol can prevent that death from ever occurring in the first place.”

Source: HealthDay

Smart Ways To Lower Your Risk Of Alzheimer’s

By the year 2050, the number of Americans over 65 who are living with Alzheimer’s disease is expected to approach 14 million, according to the Alzheimer’s Association. Because the brain changes in Alzheimer’s may start years or even decades before symptoms emerge, many researchers, doctors, and advocates focus on trying to prevent the disease before it begins. Here’s what they advise.

Protect your heart

A 2020 international medical review identified 12 major risk factors for dementia, and four were directly related to heart health: high blood pressure, obesity, diabetes, and smoking. “We know that what’s bad for the heart is bad for the brain,” says John Morris, MD, FAAN, endowed professor of neurology at Washington University in St. Louis’ Knight Alzheimer Disease Research Center. “When we look at lifestyle factors that might help prevent Alzheimer’s disease, there’s a lot of interest in heart health, diet, and staying very active.” Your doctor can suggest medication and lifestyle changes to get your blood pressure and cholesterol to healthy levels. If you are overweight or obese, ask your doctor for guidance in losing weight, and talk with a nutritionist about a healthy eating plan. If you have diabetes, work closely with your doctor to manage your blood sugar levels. And if you smoke, talk to your doctor about how to quit.

Know your risk factors

Older Black Americans have higher rates of dementia than non-Hispanic Whites, and Black Americans also have higher rates of high blood pressure, high cholesterol, diabetes, heart disease, and stroke. A 2015 study found that Black patients who had Alzheimer’s disease were more likely to have classic signs like beta-amyloids, as well as more frequent and more severe blood vessel disease. Ask your doctor for help in keeping your blood pressure, cholesterol, blood sugar, and weight at healthy levels.

Get moving

Inactivity is another of the 12 major dementia risk factors identified by the 2020 review. “Exercise can be the brain’s first defense against amyloid plaque, which builds up in the brains of people with Alzheimer’s disease,” says Richard Isaacson, MD, FAAN, a neurologist and director of the Alzheimer’s Prevention Clinic at Weill Cornell Medical College and New York–Presbyterian Hospital. “Burning body fat and building muscle mass can boost metabolism, which helps maintain brain health over time,” Dr. Isaacson says. Any type of activity—walking, dancing, bicycling—can make a difference. Aim for 30 minutes a day if you can.

Stay socially and mentally active

Get together regularly with family and friends; work or volunteer with community groups; meet new people; read or do puzzles daily. Even more important, take a class or learn a new skill. “Learning something new, like another language, helps build vital backup pathways in the brain,” Dr. Isaacson says.

Avoid head injury

A recent review added traumatic brain injury (TBI) to the list of modifiable risk factors. A 2018 study looked at how head trauma—both severe injury, as in a car accident or a fall, and repeated mild injury, like a concussion from sports—increases the risk of dementia. Protect yourself by wearing a seat belt, staying safe when playing sports, and treating any head injury right away.

Treat depression, hearing loss, and substance abuse

Primary risk factors for dementia include problems as varied as excessive alcohol consumption, hearing loss, and depression. A 2018 review of three dozen studies found links between hearing loss in midlife and developing dementia; if you can get hearing aids, wear them as much as possible. If you drink alcohol, do so in moderation. And if you believe you may have symptoms of depression—such as frequent or extreme sadness, self-isolating tendencies, or thoughts of harming yourself—reach out to anyone you can for help: friends, family, co-workers, your doctor, or services like the National Suicide Prevention Lifeline or the Substance Abuse and Mental Health Services Administration.

Source: Brain and Life

Time Until Dementia Symptoms Appear Can be Estimated Via Brain Scan

Tamara Bhandari wrote . . . . . . . . .

Researchers at Washington University School of Medicine in St. Louis have developed an approach to estimating when a person with no cognitive symptoms will start showing signs of Alzheimer’s dementia based on data from brain scans and the person’s age.

Researchers at Washington University School of Medicine in St. Louis have developed an approach to estimating when a person who is likely to develop Alzheimer’s disease, but has no cognitive symptoms, will start showing signs of Alzheimer’s dementia.

The algorithm, available online in the journal Neurology, uses data from a kind of brain scan known as amyloid positron emission tomography (PET) to gauge brain levels of the key Alzheimer’s protein amyloid beta.

In those who eventually develop Alzheimer’s dementia, amyloid silently builds up in the brain for up to two decades before the first signs of confusion and forgetfulness appear. Amyloid PET scans already are used widely in Alzheimer’s research, and this algorithm represents a new way of analyzing such scans to approximate when symptoms will arise. Using a person’s age and data from a single amyloid PET scan, the algorithm yields an estimate of how far a person has progressed toward dementia — and how much time is left before cognitive impairment sets in.

“I perform amyloid PET scans for research studies, and when I tell cognitively normal individuals about positive results, the first question is always, ‘How long do I have until I get dementia?’,” said senior author Suzanne Schindler, MD, PhD, an assistant professor of neurology. “Until now, the answer I’d have to give was something like, ‘You have an increased risk of developing dementia in the next five years.’ But what does that mean? Individuals want to know when they are likely to develop symptoms, not just whether they are at higher risk.”

Schindler and colleagues analyzed amyloid PET scans from 236 people participating in Alzheimer’s research studies through Washington University’s Charles F. and Joanne Knight Alzheimer Disease Research Center. The participants were an average of 67 years old at the beginning of the study. All participants underwent at least two brain scans an average of 4½ years apart. The researchers applied a widely used metric known as the standard uptake value ratio (SUVR) to the scans to estimate the amount of amyloid in each participant’s brain at each time point.

The researchers also accessed over 1,300 clinical assessments on 180 of the participants. The assessments typically were performed every one to three years. Most participants were cognitively normal at the start of data collection, so the repeated assessments allowed the researchers to pinpoint when each participant’s cognitive skills began to slip.

Schindler spent years trying to figure out how to use the data in amyloid PET scans to estimate the age at which symptoms would appear. The breakthrough came when she realized that amyloid accumulation has a tipping point and that each individual hits that tipping point at a different age. After this tipping point, amyloid accumulation follows a reliable trajectory.

“You may hit the tipping point when you’re 50; it may happen when you’re 80; it may never happen,” Schindler said. “But once you pass the tipping point, you’re going to accumulate high levels of amyloid that are likely to cause dementia. If we know how much amyloid someone has right now, we can calculate how long ago they hit the tipping point and estimate how much longer it will be until they are likely to develop symptoms.”

People in the study who reached the tipping point at younger ages took longer to develop cognitive symptoms than those who reached it later in life. Participants who hit the tipping point at age 50 typically took nearly 20 years to develop symptoms; those who hit it at age 80 took less than 10 years.

“When we look at the brains of relatively young people who have died with Alzheimer’s, they typically look pretty healthy, other than Alzheimer’s,” Schindler said. “But older people more frequently have damage to the brain from other causes, so their cognitive reserves are lower, and it takes less amyloid to cause impairment.”

The power of this new technique is that it requires just one brain scan, plus the person’s age. With that data, the model can estimate the time to symptom onset, plus or minus several years. In this study, the correlation between the expected age of symptom onset and the true age at diagnosis was better than 0.9 on a scale of 0 (no correlation) to 1 (perfect correlation).

After age, the genetic variant APOE4 is the strongest risk factor for Alzheimer’s dementia. People who carry one copy of the variant are two to three times more likely to develop Alzheimer’s dementia than the general population, and people who carry two copies are 10 times more likely. In this study, people with the high-risk variant hit the tipping point younger, but once that point was passed, they followed the same trajectory as everyone else.

“APOE4 seems to have a seeding effect,” Schindler said. “At very low levels, below the tipping point, you see amyloid rising in people with APOE4 while it’s not changing in people without APOE4. That means APOE4 carriers are going to hit the tipping point sooner. People with two copies of APOE4 hit the tipping point about 10 years earlier than people with no copies. But after that point, we see no difference between the APOE4 carriers and noncarriers.”

With an out-of-pocket cost of around $6,000, amyloid PET brain scans may be financially out of reach for many people. However, this algorithm could help accelerate the pace of drug development by streamlining clinical trials.

“Most participants in clinical trials designed to prevent or slow Alzheimer’s symptoms do not develop symptoms during the trials,” Schindler said. “That’s a lot of time and effort — for the participants as well as the researchers — that doesn’t yield useful data. If we could do trials only on people who are likely to develop symptoms in the next few years, that would make the process of finding therapies much more efficient.”

Source: Washington University School of Medicine

What Are Researchers Doing to Stop Dementia?

Laura Williamson wrote . . . . . . . . .

They are words nobody wants to hear: Alzheimer’s disease and dementia. As the population ages, a growing number of older adults gradually lose cherished memories and the ability to think and, ultimately, to perform even the most basic functions of daily living.

Researchers say dementias are so varied and complex, there remain more questions than answers when it comes to how to thwart them.

“This is a condition with multiple pathologies,” said Cynthia Lemere, immediate past chair of the medical and scientific advisory group of the Alzheimer’s Association. “There’s a lot of research going on right now.”

While there are many causes of dementias, much of the research revolves around Alzheimer’s, which accounts for 60%-70% of all cases. According to the Alzheimer’s Association, more than 6.2 million people are living with Alzheimer’s disease, a number expected to double by 2050.

The federal government spends about $3.1 billion annually on Alzheimer’s research. Another $250 million comes from the Alzheimer’s Association, and last year the American Heart Association announced a joint brain health research project with Bill Gates, as well as support for a global networking effort among research centers to accelerate early detection and treatment of Alzheimer’s and related dementias.

Many drugs are being tested. Some work by going after what is considered one of the hallmarks of the disease – beta-amyloid protein. When this protein builds up in the brain, it clumps together to form plaques that stick in between nerve cells, interfering with the cells’ ability to communicate.

Lemere, an associate professor of neurology in the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital and Harvard Medical School in Boston, has spent the past two decades working on an Alzheimer’s vaccine and antibodies that would attack amyloid plaques.

While trials have shown some potential, it has been difficult to get sufficient amounts of antibodies to cross the blood-brain barrier, she said. Nonetheless, “there are three or four drugs in this class coming down the pipeline that look promising.” A drug that targets amyloid plaque received conditional approval from the Food and Drug Administration this summer and requires further testing to verify its benefits.

A newer area of investigation focuses on drugs to stop the spread of a protein called tau, needed to stabilize the structure of nerve cells. In the brains of people with Alzheimer’s disease, tau changes its structure and aggregates inside the cells, causing tangles to form. The tangles block nutrients and any communication from moving through the cells, which eventually die. That’s when symptoms appear.

“Alzheimer’s disease doesn’t start when you begin to see memory loss. It starts 15-25 years earlier, when these plaques and tangles are forming,” Lemere said. “When you have them both for a long period of time, neurodegeneration starts.”

So far, researchers have seen the best results with patients who are in the earliest stages of Alzheimer’s, Lemere said. “Previous clinical trials have shown that these drugs do not work well for people with moderate to severe Alzheimer’s disease. If someone has already lost 40% of their hippocampal neurons, clearing plaque won’t bring those back. That’s why we still need to continue to find ways to help those in later stages of the disease.”

What’s causing beta-amyloid to accumulate in the first place remains unclear. Some believe it may be an immune system response to viral infections, such as herpes, and may even be linked to the bacteria in gum disease.

“It turns out that amyloid plays a role in protecting the brain from infection,” said Dr. Mitchell Elkind, immediate past president of the American Heart Association. He is a professor of neurology and epidemiology at Columbia University Irving Medical Center in New York City.

When an infection attacks the brain, beta-amyloid may be overproduced as part of an immune response, he said. One avenue of investigation hypothesizes that anti-viral agents could therefore prevent Alzheimer’s or slow progression of the disease based on the theory that “if we eliminate the inciting insult of the infection, perhaps we can decrease the amount of amyloid. That’s an exciting possibility.”

Studying COVID-19 may help, Elkind said. “For those of us interested in the concept that infections may worsen dementia, COVID provides a great model because there is so much of it around. It can help us answer the question of whether a virus can cause long-term cognitive decline. We don’t know yet.”

When viruses and bacteria activate the immune system, they also produce inflammation, which researchers believe contributes to plaque development.

“Inflammation is a hot button now for Alzheimer’s disease research,” Elkind said. Investigators are exploring whether anti-inflammatory agents can be used to ward off symptoms.

Lemere said she believes the most promising approach may be combinations of drugs that help the immune cells in the brain do their job while tamping down inflammation.

“That is going to be the wave of the future,” she said. “Maybe an anti-inflammatory agent with a tau antibody to prevent the downstream neurodegeneration.”

But even if researchers succeed in developing drugs that clear the brain of amyloid plaques and tau tangles, it won’t stop other forms of dementia, said Dr. Mary Sano, director of the Alzheimer’s Disease Research Center at Mount Sinai Health System in New York City.

About 10% of dementias are vascular – they’re linked to strokes or issues with poor blood flow to the brain. Others have mixed dementia, which can be a combination of Alzheimer’s, vascular and other less common types of dementia.

Sano’s center works with people who often develop dementias related to Type 2 diabetes and heart disease risk factors, such as high blood pressure, and these “have a very different profile of cognitive deficits.” For example, people with diabetes begin with greater problems with executive functions, such as the ability to plan and organize. Memory may be less impaired.

Lifestyle behaviors remain an important avenue for preventing vascular dementia, she said. Controlling blood pressure, cholesterol and blood sugar levels and making other lifestyle changes, such as quitting smoking, exercising, eating a nutritious diet and losing weight – metrics the AHA has dubbed Life’s Simple 7 – all have been shown to help maintain good brain health as people age.

This has to start early, Elkind said. “It’s not your blood pressure in your 70s and 80s that causes dementia, but what it was in your 40s and 50s.”

One of the best things people can do is exercise, Lemere said. “It promotes cardiovascular health, which is related to brain health. It’s anti-inflammatory and it promotes better sleep. Lack of sleep is a risk factor for Alzheimer’s disease, and exercise is one of the biggest ways people can stave off or reduce their risk for dementia.”

Source: American Heart Association

Some Diabetes Meds Might Also Lower Alzheimer’s Risk

Amy Norton wrote . . . . . . . . .

Older adults who take certain diabetes drugs may see a slower decline in their memory and thinking skills, a new study suggests.

Researchers in South Korea found that among older people who’d been having memory issues, those using diabetes drugs called DDP-4 inhibitors typically showed a slower progression in those symptoms over the next few years. That was compared with both diabetes-free older adults and those taking other diabetes medications.

People on DDP-4 inhibitors also showed smaller amounts of the “plaques” that build up in the brains of people with Alzheimer’s disease.

Experts cautioned that the findings do not prove the drugs can prevent or delay dementia.

To do that, researchers would need to conduct clinical trials that directly test the medications, said Dr. Howard Fillit, chief science officer for the nonprofit Alzheimer’s Drug Discovery Foundation in New York City.

But, he said, the study adds to evidence that certain existing medications — including some for diabetes or high blood pressure — could be “repurposed” for protecting the aging brain.

In fact, other diabetes medications, such as metformin and GLP-1 agonists, are already being studied for slowing down declines in memory and thinking skills.

There has been less research, Fillit said, into DDP-4 inhibitors — which include oral medications like sitagliptin (Januvia), linagliptin (Tradjenta), saxagliptin (Onglyza) and alogliptin (Nesina). They share a similarity with GLP-1 agonists, in that they act on the same “pathway” in the body.

Fillit explained that DDP-4 inhibitors work by boosting blood levels of GLP-1, a gut hormone that stimulates insulin release. Insulin is a hormone that regulates blood sugar.

People with diabetes are resistant to insulin, which results in chronically high blood sugar levels. Some studies have found that people with Alzheimer’s also have problems with insulin resistance — and researchers have speculated that may contribute to the brain degeneration seen in the disease.

But Fillit said that diabetes medications might have effects beyond improving insulin resistance.

Animal research has suggested DDP-4 inhibitors can reduce brain inflammation and protect brain cells from Alzheimer’s-like injury.

For the current study, researchers led by Dr. Phil Hyu Lee of Yonsei University College of Medicine in Seoul reviewed the cases of 282 patients who had come to their clinic with complaints about their memory and thinking abilities. Brain scans had shown all had evidence of amyloid — the protein that makes up Alzheimer’s-related plaques.

Of those patients, half had diabetes: 70 were taking a DDP-4 inhibitor, and 71 were using other diabetes drugs, most often metformin and sulfonylureas.

On average, the researchers found, patients on DDP-4 inhibitors had less amyloid buildup than either the diabetes-free patients or those on other diabetes medications. And over the next few years, they also showed a slower decline on tests of memory and thinking.

The findings were published online in the journal Neurology.

Maria Carrillo, chief science officer for the Alzheimer’s Association, stressed that the study cannot prove DDP-4 inhibitors slow down the dementia process.

One of the study’s limitations, she noted, is that patients’ amyloid levels were only measured at the start. So it’s not clear whether those on DDP-4 inhibitors had a slower accumulation of brain plaques over time.

It’s well known, Carrillo said, that people with diabetes have a higher risk of developing Alzheimer’s than those without diabetes — though the reasons are not fully clear, she added.

Insulin resistance, as well as high blood sugar, may partly explain it, according to the Alzheimer’s Association. Carrillo noted that this study did not look at patients’ long-term blood sugar control — and whether that had any role in their rates of decline over time.

“There is some rationale for looking at these diabetes drugs in people with Alzheimer’s,” Carrillo said.

But like Fillit, she said only randomized clinical trials — where patients are randomly assigned to take a DDP-4 inhibitor or not — can prove whether there are benefits.

One question for future studies, Fillit said, is whether DDP-4 inhibitors can slow mental decline in people without diabetes, or only those with the disease.

Because Alzheimer’s is so complex, Fillit said it is likely that medication combinations — aimed at different mechanisms behind the disease — will prove most effective at treating or preventing the disease.

Both of the nonprofits encourage people to eat a healthy diet, exercise, avoid smoking and engage in mentally stimulating activities to help keep their bodies and minds in good shape as they age.

Source: HealthDay