Early Alzheimer’s Detection Up to 17 years in Advance

A sensor identifies misfolded protein biomarkers in the blood. This offers a chance to detect Alzheimer’s disease before any symptoms occur. Researchers intend to bring it to market maturity.

The dementia disorder Alzheimer’s disease has a symptom-free course of 15 to 20 years before the first clinical symptoms emerge. Using an immuno-infrared sensor developed in Bochum, a research team is able to identify signs of Alzheimer’s disease in the blood up to 17 years before the first clinical symptoms appear. The sensor detects the misfolding of the protein biomarker amyloid-beta. As the disease progresses, this misfolding causes characteristic deposits in the brain, so-called plaques.

“Our goal is to determine the risk of developing Alzheimer’s dementia at a later stage with a simple blood test even before the toxic plaques can form in the brain, in order to ensure that a therapy can be initiated in time,” says Professor Klaus Gerwert, founding director of the Centre for Protein Diagnostics (PRODI) at Ruhr-Universität Bochum. His team cooperated for the study with a group at the German Cancer Research Centre in Heidelberg (DKFZ) headed by Professor Hermann Brenner.

The team published the results obtained with the immuno-infrared sensor in the journal “Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association”. This study is supported by a comparative study published in the same journal on 2 March 2022, in which the researchers used complementary single-molecule array (SIMOA) technology.

Early detection of symptom-free people with a high risk of Alzheimer’s disease

The researchers analysed blood plasma from participants in the ESTHER study conducted in Saarland for potential Alzheimer’s biomarkers. The blood samples had been taken between 2000 and 2002 and then frozen. At that time, the test participants were between 50 and 75 years old and hadn’t yet been diagnosed with Alzheimer’s disease. For the current study, 68 participants were selected who had been diagnosed with Alzheimer’s disease during the 17-year follow-up and compared with 240 control subjects without such a diagnosis. The team headed by Klaus Gerwert and Hermann Brenner aimed to find out whether signs of Alzheimer’s disease could already be found in the blood samples at the beginning of the study.

The immuno-infrared sensor was able to identify the 68 test subjects who later developed Alzheimer’s disease with a high degree of test accuracy (0,78 AUC, Area under Curve). For comparison, the researchers examined other biomarkers with the complementary, highly sensitive SIMOA technology – specifically the P-tau181 biomarker, which is currently being proposed as a promising biomarker candidate in various studies. “Unlike in the clinical phase, however, this marker is not suitable for the early symptom-free phase of Alzheimer’s disease,” as Klaus Gerwert summarises the results of the comparative study. “Surprisingly, we found that the concentration of glial fibre protein (GFAP) can indicate the disease up to 17 years before the clinical phase, even though it does so much less precisely than the immuno-infrared sensor.” Still, by combining amyloid-beta misfolding and GFAP concentration, the researchers were able to further increase the accuracy of the test in the symptom-free stage to 0,83 AUC.

Start-up aims to bring immuno-infrared sensor to market maturity

The Bochum researchers hope that an early diagnosis based on the amyloid-beta misfolding could help to apply Alzheimer’s drugs at such an early stage that they have a significantly better effect – for example, the drug Aduhelm, which was recently approved in the USA. “We plan to use the misfolding test to establish a screening method for older people and determine their risk of developing Alzheimer’s dementia,” says Klaus Gerwert. “The vision of our newly founded start-up betaSENSE is that the disease can be stopped in a symptom-free stage before irreversible damage occurs.” Even though the sensor is still in the development phase, the invention has already been patented worldwide. BetaSENSE aims to bring the immuno-infrared sensor to market and have it approved as a diagnostic device so that it can be used in clinical labs.

Clinical trials with Alzheimer’s drugs often fail

Approved by the FDA in the USA in spring 2021, the drug Aduhelm has been shown to clear amyloid-beta plaques from the brain. However, previous studies showed it had only a minor effect on clinical symptoms such as memory loss and disorientation. Consequently, the European Medicines Agency decided in winter 2021 not to approve the drug in Europe. “Up to now, clinical trials for Alzheimer’s drugs have been failing by the dozen, apparently because the established plaque tests used in the trials don’t flag up the disease in time,” says Gerwert. “It seems that once plaques are deposited, they induce irreversible damage in the brain.” In the tests used to date, the plaques are either detected directly in the brain with the complex and expensive PET scan technology or indirectly determined in a less complex way using protein biomarker concentrations in invasively obtained cerebrospinal fluid with ELISA or mass spectrometry technology. In contrast to established plaque diagnostics, the immuno-infrared sensor indicates the earlier misfolding of amyloid-beta, which causes the later plaque deposition. “However, it is still controversially discussed whether this misfolding is the cause of Alzheimer’s disease or if it’s just an accompanying factor,” points out Gerwert. “For the therapeutic approach, this question is crucial, but it is irrelevant for the diagnosis. The misfolding indicates the onset of Alzheimer’s disease.”

“The exact timing of therapeutic intervention will become even more important in the future,” predicts Léon Beyer, first author and PhD student in Klaus Gerwert’s team. “The success of future drug trials will depend on the study participants being correctly characterised and not yet showing irreversible damage at study entry.”

Biomarkers for Parkinson’s and ALS

Misfolded proteins play a central role in many neurodegenerative diseases, such as Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS). As the researchers have showed, the immuno-infrared sensor can in principle also be used to detect other misfolded proteins, such as TDP-43, which is characteristic of ALS. They don’t measure the concentration of a specific protein, but detect its misfolding using disease-specific antibodies. “Most importantly, this platform technology enables us to make a differential, precise biomarker-based diagnosis in the early stages of neurodegenerative diseases, in which the currently applied symptom-based diagnosis is very difficult and prone to errors,” stresses Gerwert.

Source: Ruhr-Universität Bochum Germany





Research Spots Gene That Raises Alzheimer’s Risk for Women

Researchers studying genes involved in Alzheimer’s disease have identified a new gene, called MGMT, that increases risk for this common dementia in women.

“This is one of a few and perhaps the strongest associations of a genetic risk factor for Alzheimer’s that is specific to women,” said co-senior study author Lindsay Farrer, chief of biomedical genetics at Boston University School of Medicine.

For the new study, a team from the University of Chicago and Boston University School of Medicine looked for genetic links using two unrelated datasets and different methods.

One dataset was from a large family of Hutterites, a central European group whose isolated culture and small gene pool have made it a popular focus for studying genetic determinants of disease. All the people studied for Alzheimer’s in this data were women.

The team also analyzed genetic data from a pool of 10,340 women who lacked APOE4. That gene, a well-known Alzheimer’s risk factor, is carried by about 60% of people with European ancestry and about 26% of the general population.

For both sets of data, the new gene MGMT was significantly associated with developing Alzheimer’s disease.

“This finding is particularly robust because it was discovered independently in two distinct populations using different approaches,” Farrer said. “While the finding in the large dataset was most pronounced in women who don’t have APOE4, the Hutterite sample was too small to evaluate this pattern with any certainty.”

Alzheimer’s disease is the most common cause of dementia and affects more than 5.8 million people in the United States.

“This study highlighted the value of founder populations for genetic mapping studies of diseases like Alzheimer’s,” said co-senior study author Carole Ober, chairwoman of human genetics at the University of Chicago.

Additional study will be needed to understand why MGMT influences Alzheimer’s risk in women. The authors noted that the study demonstrates the importance of searching for risk factors that may be specific to one gender.

The findings were published in Alzheimers & Dementia: The Journal of the Alzheimer’s Association.

Source: HealthDay



What People With Early-Onset Dementia Want You to Know

Dennis Thompson wrote . . . . . . . . .

An elevator encounter that happened to Laurie Waters highlights the daily plight faced by early-onset Alzheimer’s patients like her.

Waters, 57, was stuck in an elevator at an Alzheimer’s convention with other folks who were growing loud and excited — and the situation was getting to her.

“I was starting to get panic-stricken, being in that enclosed space. And one gentleman was like, ‘Well, what’s the matter with you?'” Waters recalled. “I said, ‘I’m actually living with Alzheimer’s.’ And this woman next to him said, ‘You know, that’s really mean to say that.'”

June is Alzheimer’s & Brain Awareness Month, and people like Waters are taking the opportunity to share what they’d like others to know about what it’s like to live with a dementia.

Her elevator tale illustrates two important lessons — younger people can have dementia and people with this disease would really rather not debate their diagnosis or be told they don’t look like they have Alzheimer’s.

“I look young, and people even in the Alzheimer’s community who are around it still don’t recognize younger-onset,” said Waters, who lives in Clover, S.C. “It’s everywhere. I’ve had doctors who have sat there, who haven’t met me before, just look at me and be like, ‘Are you sure you’re diagnosed with Alzheimer’s?'”

The frustration for Deborah Jobe comes from folks who talk about her as though she isn’t there.

“My husband and I will be in a room and people will ask him, you know, ‘She looks pretty good, how is she doing?'” said Jobe, 55, of St. Louis, who has an early-onset form of dementia called posterior cortical atrophy.

“I’m like, ‘Hello! Right here! You can ask me. It’s OK. I don’t mind,'” Jobe said, laughing. “I’m still here. I’m still human. Please address to me and if I can’t answer, I’m sure he’ll step in and help.”

The upshot from Waters and Jobe — people with Alzheimer’s are still people.

“One of the common themes I hear over and over again is that how the diagnosis does not define who they are,” said Monica Moreno, senior director of care and support with the Alzheimer’s Association, who works with early-stage families in the wake of their diagnosis.

“It’s not uncommon that when people hear that someone has been diagnosed, they immediately think about the end stage of the disease, where an individual may not be communicative and may not necessarily be aware of their surroundings,” Moreno said.

“And while we know that that may be that’s where the disease leads to, in the early stage of the disease individuals still want to live a meaningful life and they know that they still have things to contribute to society,” she said.

First signs of trouble

Waters received her diagnosis in 2017, when her husband noticed that she wouldn’t quit working.

“I wouldn’t leave my office. I used to work for a pharmaceutical company, and I used three computers in my office going through patient records,” Waters recalled. “And I could fly through a patient’s record in, like, five to 15 minutes.

“All of a sudden, it was taking me a half-hour, 45 minutes to an hour just to get through one record,” Waters continued. “My husband noticed I wasn’t even coming out of my office for coffee or lunch or dinner. I was working eight to 12 hours a day just to get work done. And when I had to go into the office to train people, I couldn’t even remember some of the people’s names that I knew for years. It was horrible.”

Jobe had to walk away from a high-powered career as a customer success manager for global companies following her own diagnosis two years ago.

“I would be in front of governance boards, executive management, to do a presentation and just find myself stopping,” Jobe said. “Literally, the words were in my head but I couldn’t get them out, or the wrong words would come out. And so I would joke and I would say, ‘You know, I’m sorry, let me take a step back, I haven’t had enough coffee today.'”

She also found herself struggling to keep up with new product updates, never mind explaining them to clients.

“I just couldn’t grasp it,” Jobe said. “I’ve been in this industry for over 30 years and I just couldn’t grasp it. I would have to ask questions over and over.”

Both women’s lives are different now, as they’ve adapted to their illness.

For example, Jobe’s husband uses laminated cards to help her around the house — “The dishes are clean,” or “The stove is hot.” Jobe can’t drive or cook or ride a bike, and often forgets to eat.

But she still loves new technology and word games and creating art. She’s still living her life.

“So don’t treat me differently unless I ask you to in some way — meaning like, OK, you know, slow down a little bit more,” Jobe said. “I’m still me. I’m still who I am before. Some days, maybe it doesn’t show. But the heart of me, and the soul of me is.”

Patience and understanding

Jobe and Waters and other Alzheimer’s and dementia patients have a few other things they would like others to know, to help make their lives less frustrating.

Dementia sometimes leads Jobe to act in ways that don’t reflect her true self, for example.

“I do have bad days where I’m maybe more agitated or defensive or confused,” Jobe said. “My husband sees these days coming up before I do. I get what he calls crazy eyes, and it starts before I realize that it’s happening.

“So maybe I’m doing something that’s out of character for me, but it’s not because I want to do it to hurt somebody or get mad at somebody,” Jobe continued. “Sometimes I can’t help it.”

People dealing with a person with Alzheimer’s or dementia also can help by being very patient with them. Waters recalled a day recently where she couldn’t for the life of her figure out how to scan a document.

“Now you’re talking about somebody who used to work with three computer screens,” Waters said. “I sat in my office for almost an hour and a half trying to figure out how do I scan this document into my computer. Couldn’t do it.

“People are looking at me and I’m like, I have to now explain to all these people who are looking at me like, ‘What do you mean you can’t scan a document? What’s wrong with you? You don’t look like you have anything wrong with you. You don’t look like you have Alzheimer’s. Are you crazy?'” Waters continued.

Jobe agrees.

“I don’t think as fast as I did before, which really frustrates me,” Jobe said. “I’m like, give me a minute. Let me try to process it first, and then I can answer it. Or maybe I’ll need you to break it down into something a little more simple.”

The very best way that a person can help someone with Alzheimer’s or dementia is by staying in touch and learning all you can about the illness, Moreno said.

“When the diagnosis is shared with others, it really does test relationships,” Moreno said. “And it’s not uncommon for friends to kind of step back and really not engage with the person living with the disease in the family anymore. And there really isn’t a reason for that.

“A lot of times it’s just because they don’t understand the disease. They don’t understand the progression,” Moreno continued. “And if they just took some time to educate themselves, they can get a better understanding of the disease and how to support that individual — to stay friends with them and engage with them and help them live the best life they can for as long as they can.”

Source: HealthDay

The 3 Midlife Factors That Raise Your Odds for Alzheimer’s

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

Certain lifestyle factors can sway the risk of dementia, and a new study points to the top threats to Americans these days: obesity, physical inactivity and lack of a high school diploma.

Researchers found that in just the past decade, there has been a shift in the most important modifiable risk factors for dementia in the United States. In 2011, the big three were physical inactivity, depression and smoking.

Today, lack of exercise is still among the top three, but the other spots have been replaced by obesity in middle-age and low education levels (not graduating from high school).

At the same time, the study found, that top three is not one-size-fits-all: The leading modifiable risk factors for dementia vary somewhat according to race and ethnicity.

Obesity was the No. 1 factor among white, Black and Native American adults, while lack of exercise was the top threat to Asian Americans. Among Hispanic Americans, meanwhile, low educational attainment emerged as the top modifiable risk factor.

“Our results suggest that people may be able to reduce their risk of developing Alzheimer’s and [other types of] dementia by engaging in a healthy lifestyle,” said researcher Deborah Barnes, a professor of psychiatry at the University of California, San Francisco.

The biggest risk factor for Alzheimer’s and other forms of dementia is older age, which people obviously cannot change. Genetic susceptibility is another major player; people who carry a gene variant called APOE4, for example, have a higher likelihood of developing Alzheimer’s than non-carriers do.

But it’s been estimated that about 40% of dementia cases worldwide can be attributed to modifiable risk factors, said Rebecca Edelmayer, senior director of scientific engagement for the Alzheimer’s Association.

Those include the top three found in this study, plus factors such as high blood pressure, diabetes, heavy drinking and hearing loss.

The reasons for those links are not fully clear, said Edelmayer, who was not involved in the new research. But cardiovascular health is thought to be one pathway. Obesity, high blood pressure, diabetes, smoking and a sedentary lifestyle can all damage blood vessels that feed not only the heart, but the brain.

“The strongest data we have suggest that what’s good for your heart is good for your brain,” Edelmayer said.

As for education, researchers think that may help via what’s called the “cognitive reserve” hypothesis: People with more education may be better equipped to withstand the pathological brain changes seen in dementia, and maintain their memory and thinking abilities for a longer time.

The current findings were published in JAMA Neurology. They’re based on more than 378,000 U.S. adults who took part in an annual government health survey.

Overall, the researchers estimate, 37% of dementia cases nationally are linked to any of eight modifiable risk factors: midlife obesity, inactivity, lower educational attainment, depression, high blood pressure, diabetes, smoking and hearing loss.

One reason, Barnes said, is sheer prevalence. Obesity has become much more common over the past decade, so it is contributing to more cases of dementia.

Meanwhile, she said, recent studies have suggested the link between low education levels and dementia is stronger than previously thought. So the researchers estimate that factor is contributing to more dementia cases among Americans.

But the relative importance of those factors among different groups of Americans does differ. Along with the differences seen among racial/ethnic groups, men and women showed some variance. Modifiable risk factors played a bigger role in men’s dementia risk — with 36% of cases tied to those factors, versus 30% among women.

Depression was also a bigger contributor for women, compared with men. Among women, almost 11% of dementia cases could be tied to a lifetime history of depression, according to co-researcher Dr. Roch Nianogo, of the University of California, Los Angeles School of Public Health.

Nearly one-quarter of women in the study said they’d been diagnosed with depression at some point.

Edelmayer said that research is now moving beyond finding associations to testing ways to curb dementia risk.

“We think that adopting a combination of healthy behaviors may be most effective,” Edelmayer said.

The Alzheimer’s Association is funding a trial called U.S. POINTER, which is testing that combo approach among seniors at increased risk of dementia. The lifestyle measures include exercise, mentally stimulating activities and better control of high blood pressure and diabetes.

It’s critical, Edelmayer said, that studies recruit people of color, who have historically been underrepresented in medical research. As this study shows, she noted, the top modifiable risk factors for dementia vary among different groups of Americans.

Source: HealthDay

‘Good’ Cholesterol in Brain May Help Keep Alzheimer’s at Bay

Higher levels of “good” cholesterol in the fluid surrounding your brain and spinal cord may help protect you from Alzheimer’s disease, a new study suggests.

“This study represents the first time that small HDL particles in the brain have been counted,” said study co-author Dr. Hussein Yassine. He is an associate professor of medicine and neurology at the University of Southern California’s Keck School of Medicine in Los Angeles.

For the study, Yassine and his colleagues analyzed concentrations of high-density lipoproteins (HDL) — often referred to as “good cholesterol” — in the cerebrospinal fluid of 180 healthy volunteers with an average age of nearly 77.

The study linked a higher number of small HDL particles in cerebrospinal fluid with two key indicators that they might protect against Alzheimer’s.

One indicator is better performance on tests of memory and thinking (or “cognitive”) skills. Of 141 participants who completed a series of these cognitive tests, those with higher levels of small HDL particles in their cerebrospinal fluid had better scores. And that was independent of age, sex, education or whether they carried the APOE4 gene, which boosts Alzheimer’s risk.

The link was even stronger among those who had no cognitive impairment, the findings showed.

The other indicator of a protective effect is that people with higher levels of small HDL particles also had higher levels of a peptide called amyloid beta 42 in their cerebrospinal fluid.

Even though the peptide contributes to Alzheimer’s disease when it misfolds and clumps onto neurons, a higher level of it circulating around the brain and spine has been linked to a lower risk for the disease, according to the report published online in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

The results suggest that small HDL particles may point the way to treatments for early Alzheimer’s, long before mental decline occurs.

“They may be involved with the clearance and excretion of the peptides that form the amyloid plaques we see in Alzheimer’s disease, so we speculate that there could be a role for these small HDL particles in prevention,” Yassine said in a university news release.

Before the onset of mental impairment, these oils — or small HDL particles — are lubricating the system and keeping it healthy, he explained.

“You’ve got a time to intervene with exercise, drugs or whatever else to keep brain cells healthy,” Yassine said. “We still need to understand the mechanisms that promote the production of these particles, in order to make drugs that increase small HDL in the brain.”

Source: HealthDay