Posted November 2, 2023
From the Eureka Blog. Authored by Regina Kelder
Below is the text from an article included on the Eureka blog which provides an overview of the need for a multi-pronged approach to stopping Alzheimer’s disease. The work of Dr.’s Rudy Tanzi and David Holtzman, and the late Stephen Wagner, of the Cure Alzheimer’s Fund Research Leadership Group, is referenced in this article and includes quotes from Rudy and David.
“For decades now, Alzheimer’s researchers have wrestled with a chicken or egg question involving the proteins most commonly associated with this memory-ravaging condition. They know that an overproduction or decreased clearance of amyloid beta, a protein associated with neural growth and repair, forms hard plaques in the brains of Alzheimer’s disease (AD) patients. And they know that tau proteins, also found in brain cells, can become “toxic” and form spaghetti-like tangled strings.
What science has been on the fence about is whether abnormal build-up of amyloid plaques or dysfunctional tau drive the neurodegeneration found in the brains of people with AD, or whether both are merely consequences of an exceptionally complex disease process caused by other factors.
While a definitive answer to this question continues to elude neuroscientists, the pendulum shifted strongly toward amyloid beta as an upstream cause of degeneration after scientists showed that therapeutic antibodies targeting amyloid could, in specific subgroups of Alzheimer’s patients, target amyloid plaques and remove them. For the first time in decades, a window opened to the possibility of one day controlling this horrible disease. While the antibody drugs are not a cure or even able to restore memories destroyed by Alzheimer’s, they do modestly but significantly slow progression of the condition in patients with mild AD, a big step forward for clinicians with little to offer patients. There are now two anti-amyloid monoclonal antibodies available commercially in the US, Aduhelm and Leqembi, and one under consideration in the EU and Japan. There are currently more than 140 antibody drugs for AD being tested in clinic trials.
The drugs are expensive and in the case of Leqembi can cause, in rare instances, brain swelling and serious brain bleeds. But therapeutic antibodies still represent the biggest step forward in a field largely known for its setbacks; more than 200 investigational programs for different kinds of disease-modifying therapies have failed or been abandoned since 2010 alone. There are multiple reasons for this. In some cases, the treatments occurred too late in the course of the disease, in others, the targets were wrong or the dosages inappropriate. But arguably the biggest reason has been a failure to grasp a clear understanding of the complex and disordered pathology associated with Alzheimer’s, and how to stop it.
One scientist who is clearly a believer that amyloid is the main driver of Alzheimer’s is Dr. Rudolph Tanzi, PhD, Director of the Genetics and Aging Research unit at Massachusetts General Hospital (MGH and a Professor of Neurology at Harvard. In 1987, his team, among others, reported the identification of the gene that makes beta-amyloid on chromosome 21, where rare mutations can cause early-onset familial Alzheimer’s disease. The gene codes for amyloid beta-protein precursor or APP that can lead to an uptick in amyloid B peptide in the brain. The production of longer, stickier forms of this peptide can accumulate in the brain and form amyloid plaques, a hallmark of people with AD. Dr. Tanzi discovered another defective gene in 1995 called presenilin 2 that alters calcium signaling in cells. It also leads to amyloid plaques and death of neurons.
Since his seminal discoveries, Tanzi has never wavered from the amyloid hypothesis, but it took him 20 years to realize that it wasn’t enough to target the toxic proteins in the brain of full-blown Alzheimer’s disease patients. It must be done much earlier to help prevent the disease, preferably before symptoms. And it’s not just these toxic proteins that are the culprits. While the amyloid plaques and tau tangles inflict damage in the earliest stages of disease, it is the near continuous neuroinflammation triggered by malfunctioning microglia—specialized immune cells that reside in the central nervous system—that arguably do the most damage.
Normally the job of microglia is to sweep away neurological debris, including amyloid residue. But in Alzheimer’s disease they go into overdrive and kill off healthy neurons, too, accelerating the course of the disease in the process. This chronic immune response by microglia is thought by many scientists to be the third core pathological feature of Alzheimer’s.
“In my mind, it’s very clearcut,” says Dr. Tanzi. “You need safe drugs to hit amyloid plaques and tau tangles early in life to prevent the disease. If you are too late for that, have to put out the fire. You have to stop the neuroinflammation, or at least give the neurons a fireproof vest to protect them from dying.”
In 2008, Tanzi’s lab discovered the first AD gene associated with microglia neuroinflammation, called CD33, a surface cell receptor found in microglia (and other immune cells) that is more abundant in people with Alzheimer’s disease. Increased levels of CD33 are connected to disease severity. Five years later, he discovered that when CD33 is highly expressed, it can damage neurons by signaling microglia to trigger neuroinflammation.
Another gene predominantly expressed by microglia, known as TREM2, also plays a complex role in neuroinflammation. Normally, it encodes for a protein that regulates the response by microglia to infection and injury, including clearing excessive amounts of amyloid and tau from the brain. But in 2012, University of London scientist Dr. Rita Guerreiro discovered that variations in TREM2 actually decrease the function of the protein and potentially increase the risk of AD three-fold.
Both CD33 and TREM2 interact in important ways, too. Four years ago, Tanzi’s lab published animal data describing how the crosstalk of these genes appear to play a role in neuroinflammation, with CD33 turning on inflammation and TREM2 shutting it down. They concluded that if you silence CD33 but keep TREM2 on you could potentially reduce the toxic inflammation that accelerates AD.
Today around 20% of the disease-modifying drugs in Phase III trials for AD have immunomodulating actions that target microglia, with the vast majority aimed at TREM2.
“There is no surprise that the vast majority of new Alzheimer’s genes coming out of genome-wide screens are genes that control microglial activation in neuroinflammation,” said Tanzi.
Dan Rocca, PhD, a Research Leader at Charles River Laboratories and a neuroscientist by training, says there is no doubt microglia have a complex relationship with Alzheimer’s disease, adding that it can be really difficult to pull apart exactly what they do at different times during progression of the disease. “Depending on what stage you’re at, microglia can be either exacerbating the disease, or protecting you against it and alleviating some of the symptoms,” said Rocca. “They can potentially throw out lots of cytokines, which cause inflammation and death of neurons, but they can also engulf amyloid beta and so reduce those plaques.”
While TREM2 and CD33 are obvious targets for drug developers, they are not the only avenue of research. Rocca says some companies are targeting the inflammasome—a formation of danger-sensing proteins triggered when a cell becomes infected or damaged. In the brain, there is evidence that both beta amyloid and tau can trigger persistent activation of the NLRPE inflammasome, leading to chronic neuroinflammation. “There are companies that have developed small molecules that have been modified chemically to penetrate the brain. They work by targeting the inflammasome to potentially stop the adverse effects of microglia,” says Rocca.
And Dr. David Holtzman, PhD, a Professor of Neurology at Washington University in St. Louis says T cells may also interact with microglia to cause neurodegeneration. His lab published findings this year in the journal Nature showing that the adaptive immune response drives degeneration in the presence of tau. “There are so many different FDA approved drugs that influence T-cells in different autoimmune diseases and cancer,” says Holtzman. “I think it would be incredibly cool if we could begin to assess those sorts of drugs in the context of very mild AD.” Tanzi’s lab also recently published a paper in Nature Neuroscience using a mini brain organoid model of Alzheimer’s disease demonstrating how the T cells are recruited in into the brain and exacerbate Alzheimer’s pathology.
Meanwhile, a novel drug discovered by Dr. Steven Wagner from University of California at San Diego and Tanzi’s lab at MGH was found to decrease plaque formation and reduced plaque-associated inflammation in animals. The drug, known as a γ-Secretase modulator or GSM, also bypasses many of the problems that occurred when researchers tried to inhibit the enzyme. Dr. Wagner died last year, but Tanzi and colleagues are now preparing the drug for Phase 1 clinical trials in healthy adults, to assess safety.
Not surprisingly, more and pharmaceutical companies are looking for preclinical models that show microglial activation, says Dr. Susanne Bäck, PhD, Senior Manager of CNS Pharmacology at Charles River’s Kuopio, Finland site. There are several mouse models that can be used for measuring neuroinflammation in AD, says Dr. Bäck. “But it’s difficult because in most models, neuroinflammation is mainly a secondary response to amyloidβ overproduction and plaque formation and does not capture all inflammatory changes seen in human Alzheimer’s.” Her team is currently working with Dr. Rocca’s group on a project to isolate from a popular Alzheimer’s mouse model microglia cells and then looking at their expression patterns.
Tanzi believes one way forward for controlling Alzheimer’s treatment is a combination of drugs, such as a therapeutic antibody to clear the plaques and a small-molecule drug, like the gamma secretase modulator, to keep the amyloid levels down. They could be combined with other drugs to control the spread of tangles and reduce neuroinflammation. “But, for this to work, it would be best to give the antibody before people have symptoms,” he said. Tanzi is also using his lab’s “Alzheimer’s-in-a-Dish™” mini-human brain organoid models to rapidly screen for known FDA approved drugs that can clear amyloid from the brain more safely and affordably than the new amyloid antibody drugs, Leqembi and Aduhelm.
Scientists more or less agree that unless you can catch Alzheimer’s in the earliest stages, when cognitive decline is not yet apparent, you probably won’t succeed in slowing the course of the disease. But Alzheimer’s isn’t like breast or colon cancer, where reliable early detection methods find tumors and even precancerous tumors well before they spread or symptoms surface.
Still there is amazing progress being made in detecting Alzheimer’s-related proteins in the blood. A number of different blood tests are in different stages of clinical development, and there are even a few commercially available for doctors to use. The catch is that insurance companies aren’t covering them yet, so their use is sparse. One test developed by scientists at Lund University in Sweden measures one of the tau proteins (phospho-tau217) found in tangles that accumulate in the brains of AD patients. Findings published in JAMA found the test was 96% accurate in determining whether people with dementia had Alzheimer’s rather than other neurodegenerative disorders.
More recently researchers from Lund and Washington University in St. Louis collaborated to show that a form of tau in the cerebrospinal fluid known as MTBR-tau243 can be used to track progression of tau tangles in Alzheimer’s disease, which could help both in diagnosing and staging AD.
Washington University also developed a blood test that evaluates whether amyloid plaques have begun accumulating in the brain based on the ratio of two beta amyloid proteins found in the blood. The test relies on a more advanced form of mass spectrometry, a tool used in analytical chemistry, that can find forms of beta amyloid molecules in blood with a high degree of accuracy. A commercial version of the test is now CLIA-certified and available to doctors through C2N Diagnostics, a company founded by Washington University neuroscientist Randall Bateman—inventor of the test—and Holtzman.
C2N released a second test this summer that looks to be as good as PET scans and spinal taps in ruling in or out AD in patients with mild cognitive impairment. In a clinical validation study of 583 patients with cognitive impairment using amyloid PET as the reference standard, the blood test achieved an overall test performance statistic of 0.94 AUC and 88% accuracy.
Dr. Holtzman, who is also Director of the Hope Center for Neurological Disorders, said there is no doubt that blood tests, once they become more widely available, open the door to a less expensive, less invasive ways of determining if a patient qualifies for an antibody drug like Leqembi. “Right now, in order to get on a drug like that, based on the criteria used in the clinical trials, you have to show the patient not only has mild memory impairment but is also amyloid positive,” said Holtzman. “And the way they screen for amyloid positivity is either using a PET scan, which costs seven to eight thousand dollars, or a CSF test for amyloid beta and tau, which is not as easy to administer.”
Still, Dr. Holtzman said it will be years before we know if antibody treatments can slow or stop the disease in the earliest stages, when people appear clinically normal but have intermediate levels of brain amyloid.
“There are ongoing clinical trials assessing clinically normal people who have elevated amounts of amyloid disposition to see if an [antibody] will delay the onset of clinical disease,” he said. “But it’s going to take 6-9 years before we know the results of those trials.””
Published October 18, 2023, eureka, Author Regina Kelder. Below is a link to the original article.
https://www.criver.com/eureka/how-can-we-overcome-alzheimers
