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Boosting brain protein levels may slow decline from Alzheimer’s

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A study published in the journal Brain shows that increases in protein levels with new Alzheimer’s drugs can explain the slowing of cognitive impairment at least as well as the reduction in amyloid plaques. 

During a study challenging the idea that newly approved monoclonal antibodies reduce cognitive decline in Alzheimer’s patients by clearing amyloid, University of Cincinnati researchers found that the unintended increase in levels of a critical brain protein correlates equally well with cognitive benefits. 

Led by UC’s Alberto Espay, MD, the research was published in the journal Brain on Sept. 11. 

Study background 

For decades, the prevailing theory in the field has stated that a protein made up of 42 amino acids called amyloid-beta 42 (Aβ42) hardens into clumps called amyloid plaques, and those plaques damage the brain, causing Alzheimer’s disease. 

Espay and team have hypothesized that normal, soluble Aβ42 in the brain is crucial for neuron health and that the loss of Aβ42, rather than the buildup of plaques, drives Alzheimer’s. This includes published research that suggests dementia occurs not when plaque levels are high but when Aβ42 levels drop very low. 

According to Espay’s research, the transformation of Aβ42 into plaques appears to be the brain’s normal response to biological, metabolic or infectious stress. 

“Most of us will accrue amyloid plaques in our brains as we age, and yet very few of us with plaques go on to develop dementia,” said Espay, professor of neurology in the UC College of Medicine and director and endowed chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders at the UC Gardner Neuroscience Institute. “Yet the plaques remain the center of our attention in biomarker development and therapeutic strategies.” 

Study details 

Recently, several new monoclonal antibody medications designed to remove amyloid from the brain were approved after showing they lessened cognitive decline in clinical trials. 

Espay and his colleagues noticed that these drugs unintentionally increased levels of Aβ42.  

“Amyloid plaques don’t cause Alzheimer’s, but if the brain makes too much of it while defending against infections, toxins or biological changes, it can’t produce enough Aβ42, causing its levels to drop below a critical threshold,” Espay explained. “That’s when dementia symptoms emerge.” 

The team analyzed data from nearly 26,000 patients enrolled in 24 randomized clinical trials of these new antibody treatments, assessing cognitive impairment and differences in levels of Aβ42 before and after treatment. They found that higher levels of Aβ42 after treatment were independently associated with slower cognitive impairment and clinical decline.  

“All stories have two sides — even the one we have told ourselves about how anti-amyloid treatments work: by lowering amyloid,” Espay said. “In fact, they also raise the levels of Aβ42. Even if this is unintended, it is why there may be a benefit. Our study shows that we can predict changes in cognitive outcomes in anti-amyloid trials at least as well by the increases in Aβ42 as by the decreases in amyloid.” 

Espay said these findings fit well into his larger hypothesis about the root cause of Alzheimer’s, as increasing levels of Aβ42 appear to improve cognition.  

“If the problem with Alzheimer’s is the loss of the normal protein, then increasing it should be beneficial, and this study showed that it is,” he said. “The story makes sense: Increasing Aβ42 levels to within the normal range is desirable.” 

However, Espay believes these results also present a conundrum for clinicians because removing amyloid from the brain is toxic and may cause the brain to shrink faster after antibody treatment. 

“Do we give patients an anti-protein treatment to increase their protein levels? I think the end, increasing Aβ42, doesn’t justify the means, decreasing amyloid,” Espay said. Therapies that directly increase Aβ42 levels without targeting amyloid are a focus of research for Espay and his group. 

Other coauthors of the study include UC’s Jesus Abanto, Alok K. Dwivedi of Texas Tech University and Bruno P. Imbimbo of Chiesi Farmaceutici of Parma, Italy

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Young vapers perform worse in exercise testing

On average, the group of young vapers had lower ‘peak exercise capacity’ (186 watts) than the group who did not vape or smoke (226 watts) but similar capacity to the group of smokers (182 watts). This is a measure of the maximum amount of physical exertion that a person can achieve.

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Young people who vape perform worse than non-vapers in tests designed to measure their capacity for exercise, according to a study presented at the European Respiratory Society (ERS) Congress in Vienna, Austria. The research also showed that the performance of young vapers was similar to that of young smokers.

The study adds to growing evidence that long-term use of vaping is harmful and challenges the idea that vaping could be a healthier alternative to smoking.

The research was presented by Dr Azmy Faisal, senior lecturer in cardiorespiratory physiology in the department of sport and exercise sciences at Manchester Metropolitan University, UK. He said: “Previous research has shown that vaping is linked to lung inflammation and damage, and harmful changes to the blood vessels. Although, some research suggests that vaping could be used to cut back or quit smoking, we don’t yet know what longer-term vaping use does to our bodies.”

The study included 60 people in their 20s who all had normal lung function according to spirometry testing. Twenty were non-smokers and non-vapers, 20 had been vaping for at least two years and 20 had been smoking for at least two years.

Each person took part in an incremental exercise test on a static bike. This is the gold-standard for testing physical ability and how well a person copes with exercise, looking at their heart, lungs, and muscles’ responses at harder and harder levels until they reach their maximum. They were also given blood tests and an ultrasound scan to analyse how well their arteries were functioning.

On average, the group of young vapers had lower ‘peak exercise capacity’ (186 watts) than the group who did not vape or smoke (226 watts) but similar capacity to the group of smokers (182 watts). This is a measure of the maximum amount of physical exertion that a person can achieve. At peak exercise, vapers and smokers were also less able to consume oxygen on average (2.7 litres per minute and 2.6 litres per minute) compared to the non-smoking non-vaping groups (3 litres per minute).

Both vapers and smokers showed signs that their blood vessels were not working as well as the non-smoking and non-vaping group, according to the blood tests and ultrasound scans. The smokers and the vapers were more out of breath, experienced intense leg fatigue and had higher levels of lactate in their blood, a sign of muscle fatigue, even before they reached their maximum level of exercise.

Dr Faisal said: “In this study, we looked at a group of young people with no apparent signs of lung damage. Among the people who had been vaping or smoking for at least two years, we saw important differences in how well they coped with exercise. The smokers and the vapers had measurably excess breathing while using the exercise bikes. They found it harder to breath, their muscles became more fatigued, and they were less fit overall. In this regard, our research indicated that vaping is no better than smoking.”

Dr Filippos Filippidis is Chair of the ERS Tobacco Control Committee, a reader in public health at Imperial College London and was not involved in the research. He said: “Vapes are being sold cheaply and in a variety of flavours to appeal to young people. As a result, we’re seeing more and more young people take up the habit without knowing what the long-term consequences could be to their health.

“Although it’s always a challenge to know if the associations we find in these studies are causal or a result of some other systematic differences between groups, people who vape need to be aware that using these products could make them less fit and able to take part in exercise. Doctors and policymakers also need to know about the risks of vaping, and we should be doing all we can to support children and young people to avoid or quit vaping.”

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Some adverse pregnancy outcomes may increase risk of heart disease later in life

A self-reported history of gestational hypertension was associated with cardiovascular disease. Women with preeclampsia or all three adverse pregnancy outcomes also had a numerically higher prevalence of heart disease, but it did not meet the standards of statistical significance. No association was found between gestational diabetes and heart disease.

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Pregnancy-related hypertension has already been proven to lead to a number of negative health outcomes later in life, including more bothersome menopause symptoms like hot flashes, the risk of dementia, kidney problems, and stroke. A new study suggests it can also lead to cardiovascular disease during menopause. Results of the study were presented at the 2024 Annual Meeting of The Menopause Society in Chicago, USA.

In the new study involving nearly 400 women with a mean age of 81.6 years, researchers sought to assess the association between a self-reported history of preeclampsia or eclampsia, gestational hypertension, and gestational diabetes with cardiovascular outcomes in postmenopausal women.

What they found is that a self-reported history of gestational hypertension was associated with cardiovascular disease. Women with preeclampsia or all three adverse pregnancy outcomes also had a numerically higher prevalence of heart disease, but it did not meet the standards of statistical significance. No association was found between gestational diabetes and heart disease.

“Future research based on a larger sample size is needed to better understand the role adverse pregnancy outcomes may have in cardiovascular disease development and risk stratification,” says Marie Tan, lead author from Drexel University College of Medicine in Philadelphia.

More detailed results will be discussed at the 2024 Annual Meeting of The Menopause Society as part of the presentation entitled “The association between adverse pregnancy outcomes and cardiovascular disease in menopausal women: results from a cross-sectional analysis.”

“Cardiovascular disease is the number one cause of mortality in women and it’s important to study any new risk factors” says Dr. Stephanie Faubion, medical director for The Menopause Society. “Although future research is still needed, studies like this are important and remind us to thoroughly discuss a patient’s health history, including any complications or adverse outcomes during pregnancy.”

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Babies born to women consuming a high fat, sugary diet at greater risk of cardiovascular disease and diabetes in later life

Consuming a high-fat, sugary diet during pregnancy also increases the likelihood of the unborn baby becoming insulin resistant in adulthood, potentially triggering diabetes and causing cardiovascular disease. This is despite babies being a normal weight at birth.

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Babies born to pregnant women with obesity are more likely to develop heart problems and diabetes as adults due to fetal damage caused by the high-fat, high-energy diet of their mother.

That’s the groundbreaking finding from a new study published in the Journal of Physiology that shows for the first time that maternal obesity alters a critical thyroid hormone in the fetal heart, disrupting its development.

Consuming a high-fat, sugary diet during pregnancy also increases the likelihood of the unborn baby becoming insulin resistant in adulthood, potentially triggering diabetes and causing cardiovascular disease. This is despite babies being a normal weight at birth.

University of South Australia researchers identified the link by analysing tissue samples from the fetuses of pregnant baboons fed a high-fat, high-energy diet in a biomedical research institute in the United States. They then compared this to fetuses from baboons on a control diet.

Lead author, University of South Australia PhD candidate Melanie Bertossa, says the findings are significant because they demonstrate a clear link between an unhealthy diet high in saturated fats and sugar, and poor cardiovascular health.

“There has been a long-standing debate as to whether high-fat diets induce a hyper- or hypothyroid state in the fetal heart. Our evidence points to the latter,” Bertossa says.

“We found that a maternal high-fat, high-energy diet reduced concentrations of the active thyroid hormone T3, which acts like a switch around late gestation, telling the fetal heart to start preparing for life after birth. Without this signal, the fetal heart develops differently.”

Bertossa says that diets high in fat and sugar can alter the molecular pathways involved in insulin signalling and critical proteins involved in glucose uptake in the fetal heart. This increases the risk of cardiac insulin resistance, often leading to diabetes in adulthood.

“You’re born with all the heart cells you will ever have. The heart doesn’t make enough new heart muscle cells after birth to repair any damage, so changes that negatively impact these cells before birth could persist for a lifetime.

“These permanent changes could cause a further decline in heart health once children reach adolescence and adulthood when the heart starts to age.”

Senior author, UniSA Professor of Physiology Janna Morrison, says the study demonstrates the importance of good maternal nutrition in the leadup to pregnancy, not only for the mother’s sake but also for the health of the baby.

“Poor cardiac outcomes were seen in babies that had a normal birth weight – a sign that should guide future clinical practice,” Prof Morrison says.

“Cardiometabolic health screening should be performed on all babies born from these types of pregnancies, not just those born too small or too large, with the goal being to detect heart disease risks earlier.”

Prof Morrison says that if rising rates of high-fat sugary diets are not addressed, more people will develop health complications such as diabetes and cardiovascular disease, which could result in shorter life spans in the decades ahead.

“Hopefully, with the knowledge we have now about the negative health impacts of obesity, there is potential to change this trajectory.”

The researchers are currently undertaking long-term studies of babies born to women on high- fat high-energy diets to track their health over decades.

Maternal high-fat high-energy diet alters metabolic factors in the non-human primate fetal heart” is published in the Journal of Physiology and authored by researchers from the University of South Australia, University of Wyoming and Texas Biomedical Health Institute.

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