Simple Diagnostic Tool Predicts Individual Risk of Alzheimer’s

Researchers at Lund University in Sweden have developed an algorithm that combines data from a simple blood test and brief memory tests, to predict with great accuracy who will develop Alzheimer’s disease in the future.

Approximately 20-30% of patients with Alzheimer’s disease are wrongly diagnosed within specialist healthcare, and diagnostic work-up is even more difficult in primary care. Accuracy can be significantly improved by measuring the proteins tau and beta-amyloid via a spinal fluid sample, or PET scan. However, those methods are expensive and only available at a relatively few specialized memory clinics worldwide. Early and accurate diagnosis of AD is becoming even more important, as new drugs that slow down the progression of the disease will hopefully soon become available.

A research group led by Professor Oskar Hansson at Lund University have now shown that a combination of relatively easily acccessible tests can be used for early and reliable diagnosis of Alzheimer’s disease. The study examined 340 patients with mild memory impairment in the Swedish BioFINDER Study, and the results were confirmed in a North American study of 543 people.

A combination of a simple blood test (measuring a variant of the tau protein and a risk gene for Alzheimer’s) and three brief cognitive tests that only take 10 minutes to complete, predicted with over 90% certainty which patients would develop Alzheimer’s dementia within four years. This simple prognostic algorithm was significantly more accurate than the clinical predictions by the dementia experts who examined the patients, but did not have access to expensive spinal fluid testing or PET scans, said Oskar Hansson.

Our algorithm is based on a blood analysis of phosphylated tau and a risk gene for Alzheimer’s, combined with testing of memory and executive function. We have now developed a prototype online tool to estimate the individual risk of a person with mild memory complaints developing Alzheimer’s dementia within four years”, explains Sebastian Palmqvist, first author of the study and associate professor at Lund University.

One clear advantage of the algorithm is that it has been developed for use in clinics without access to advanced diagnostic instruments. In the future, the algorithm might therefore make a major difference in the diagnosis of Alzheimer’s within primary healthcare.

The algorithm has currently only been tested on patients who have been examined in memory clinics. Our hope is that it will also be validated for use in primary healthcare as well as in developing countries with limited resources”, says Sebastian Palmqvist.

Simple diagnostic tools for Alzheimer’s could also improve the development of drugs, as it is difficult to recruit the suitable study partcipants for drug trials in a time- and cost-effective manner. ”The algorithm will enable us to recruit people with Alzheimer’s at an early stage, which is when new drugs have a better chance of slowing the course of the disease”, concludes Professor Oskar Hansson.

The findings are published in Nature Medicine.

Source: https://www.lunduniversity.lu.se/

Human Brain Cells Gene-edited To reduce The Risk Of Developing Alzheimer’s Disease

Cells in the human brain could one day be edited by scientists to prevent the development of Alzheimer’s disease, a new study suggests. The causes of Alzheimer’s are still not well understood, but a leading theory is that it is triggered by the build-up of a protein called beta-amyloid outside the brain cells. Researchers from Laval University in Canada have been investigating how a key gene in human nerve cells could reduce the formation of this protein. Many variants of this gene increases beta-amyloid production, but one variant, called A673T, instead reduces it.

A673T was first discovered in 2012, and is only active in one in 150 people in Scandinavia, but those that have it are four times less likely to get Alzheimer’s. The researchers believe that switching on this gene variant in brain cells could reduce the production of beta-amyloid and thereby reduce Alzheimer’s risk. As the A673T variant doesn’t become relevant until later in life, it isn’t selected for by evolution, according to the study authors. It differs from other variants of the gene by a single DNA letter. Researchers showed that, by editing this one DNA letter, they were able to activate the A673T variant in brain cells growing in a culture dish. Jacques Tremblay and colleagues say this is the first step to proving that engineering the variant into brains could have the same benefits as inheriting it.

The team are still refining the technique before they try it on animals. The researchers initially used a CRISPR technique called base editing, which allows the direct, irreversible conversion of a DNA base into another, targeted base. However, they have now switched to a relatively new method called prime editing – a ‘search and replace‘ technique for editing genomes that directly writes new genetic information into a targeted DNA site using a fusion protein.  Working with cells in a dish they managed to edit about 40 per cent of the cells, but they think a higher proportion might be needed for it to work in a human brain.

The researchers  worked with a process known as base editing, a relatively new method that allows the direct, irreversible conversion of a DNA base into another, targeted base
Source: https://www.dailymail.co.uk/

Genetic Test To Detect Earlier Alzheimer’s

A new study published in the journal Epigenetics in February 2020 reports that changes in the methylation status of the Presenilin 1 (PSEN1) gene could help diagnose Alzheimer’s disease (AD) earlier. This study shows for the first time that methylation of this gene is a common feature in AD.

AD is a widespread dementia disorder, involving the loss of cognitive skills such as thinking, making decisions, remembering things in connection, and learning. It affects almost 50 million people the world over, mostly over the age of 60 years but a significant percentage at ages below 50 years. Furthermore, this is only a fourth of all cases, because most patients go undiagnosed.

 

The progressive and incurable nature of this disorder makes it difficult to bear for both the patient and the caregivers. The disease inevitably progresses to the point where complete care is required. Currently, available medications must be given early to have the highest odds of successfully delaying the onset of severe cognitive loss.

The PSEN1 gene is part of a protease complex that catalyzes a process called regulated intramembrane proteolysis. It is important in AD because it is responsible for cleaving the beta-amyloid fragment from the parent AβPP molecule. It is one of several polymorphic genes that regulate normal embryonic regulation but also promote the risk of AD.

Epigenetic modification is an important way to regulate gene activity in the body and can be triggered by environmental factors, including specific lifestyle and nutritional factors. The addition of methyl groups to the DNA (mostly to the cytosine) outside the actual genetic code, called methylation, is a well-known epigenetic modification. Methylation is typically a method to silence or downregulate the associated gene.

Earlier animal studies have shown that the PSEN1 gene can be downregulated, causing a condition very like AD.  However, little research has been done epigenetic modification of the human PSEN1 gene. It is established that people with AD already show altered PSEN1 behavior. The current study is the first to record the frequent occurrence of DNA methylation at this gene in humans with AD.

Source: https://www.news-medical.net/

Breakthrough In The Fight Against Alzheimer’s

In a shocking reversal, Biogen (BIIB) said that it would resurrect an Alzheimer’s drug that the company previously said had failed and will ask the Food and Drug Administration (FDA) to approve it. The company said a “new analysis of a larger dataset” showed that the drug, aducanumab, reduced clinical decline in patients with early Alzheimer’s disease on multiple measures of the drug’s effectiveness. That directly contradicts a decision in March to halt studies of the therapy based on the recommendations of an independent monitoring board that was charged with protecting patients in the study. Aducanumab’s failure sent shock waves far beyond Biogen. It was thought to be the last of a series of drugs—the previous ones, from many different drug companies, all failed—that targeted a protein in the brain called beta amyloid. After Biogen’s announcement in March, most researchers and biotechnology executives saw little hope for a drug that would help patients with Alzheimer’s disease even as cases mount.

Biogen said that it conducted a new analysis in consultation with the FDA of a larger data set from the discontinued studies. The new analysis includes additional data that became available after the previous analysis showed the studies were “futile”—that it had no chance of succeeding. Biogen said that the new data show aducanumab is “pharmacologically and clinically active” and that it reduced patients’ clinical decline based on the results of a survey called Clinical Dementia Rating-Sum of Boxes (CDR-SB), which was the main goal of both studies.

With such a devastating disease that affects tens of millions worldwide, today’s announcement is truly heartening in the fight against Alzheimer’s. This is the result of groundbreaking research and is a testament to Biogen’s steadfast determination to follow the science and do the right thing for patients,” Michel Vounatsos, Biogen’s chief executive, said in a statement. “We are hopeful about the prospect of offering patients the first therapy to reduce the clinical decline of Alzheimer’s disease and the potential implication of these results for similar approaches targeting amyloid beta.”

Al Sandrock, Biogen’s head of research and development and chief medical officer, said in his first interview about the new results that his team could only find one previous instance where a trial was stopped for futility and then it turned out to be positive. “I have to pinch myself because I almost don’t believe it yet,” Sandrock said. “It’s so amazing to have this change from March. But I’m also very, very happy because… I know people with mild cognitive impairment and I felt like I had let them all down.

By June, as Biogen analyzed the full data set, researchers started to realize that a different picture was emerging of aducanumab, Sandrock said. The reason was because of changes that Biogen had made to the study late in the game. Initially, the company worried about a potential side effectbrain swelling—and limited the dosage of the drug. But later patients were allowed to receive higher doses of the medicine.

Source: https://www.biogen.com/
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https://www.scientificamerican.com/

New Theory To Prevent Alzheimer’s

Alzheimer’s disease, the most common cause of dementia among the elderly, is characterized by plaques and tangles in the brain, with most efforts at finding a cure focused on these abnormal structures. But a University of California, Riverside, research team has identified alternate chemistry that could account for the various pathologies associated with the diseasePlaques and tangles have so far been the focus of attention in this progressive disease that currently afflicts more than 5.5 million people in the United States. Plaques, deposits of a protein fragment called beta-amyloid, look like clumps in the spaces between neurons. Tangles, twisted fibers of tau, another protein, look like bundles of fibers that build up inside cells.

The dominant theory based on beta-amyloid buildup has been around for decades, and dozens of clinical trials based on that theory have been attempted, but all have failed,” said Ryan R. Julian, a professor of chemistry who led the research team. “In addition to plaques, lysosomal storage is observed in brains of people who have Alzheimer’s disease. Neurons — fragile cells that do not undergo cell division — are susceptible to lysosomal problems, specifically, lysosomal storage, which we report is a likely cause of Alzheimer’s disease.”

An organelle within the cell, the lysosome serves as the cell’s trashcan. Old proteins and lipids get sent to the lysosome to be broken down to their building blocks, which are then shipped back out to the cell to be built into new proteins and lipids. To maintain functionality, the synthesis of proteins is balanced by the degradation of proteins.

The lysosome, however, has a weakness: If what enters does not get broken down into little pieces, then those pieces also can’t leave the lysosome. The cell decides the lysosome is not working and “stores it, meaning the cell pushes the lysosome to the side and proceeds to make a new one. If the new lysosome also fails, the process is repeated, resulting in lysosome storage.

The brains of people who have lysosomal storage disorder, another well-studied disease, and the brains of people who have Alzheimer’s disease are similar in terms of lysosomal storage,” Julian said. “But lysosomal storage disorder symptoms show up within a few weeks after birth and are often fatal within a couple of years. Alzheimer’s disease occurs much later in life. The time frames are, therefore, very different.”

Julian’s collaborative team of researchers in the Department of Chemistry and the Division of Biomedical Sciences at UC Riverside posits that long-lived proteins, including beta-amyloid and tau, can undergo spontaneous modifications that can make them undigestible by the lysosomes. “Long-lived proteins become more problematic as we age and could account for the lysosomal storage seen in Alzheimer’s, an age-related disease,” Julian said. “If we are correct, it would open up new avenues for treatment and prevention of this disease.”

Study results appear in ACS Central Science, a journal of the American Chemical Society.

Source: https://news.ucr.edu/