FDA-approved Drugs Slow or Reverse Alzheimer’s

A research team at Washington University School of Medicine in St. Louis has identified potential new treatment targets for Alzheimer’s disease, as well as existing drugs that have therapeutic potential against these targets.

The potential targets are defective proteins that lead to the buildup of amyloid in the brain, contributing to the onset of problems with memory and thinking that are the hallmark of Alzheimer’s. The 15 existing drugs identified by the researchers have been approved by the Food and Drug Administration (FDA) for other purposes, providing the possibility of clinical trials that could begin sooner than is typical, according to the researchers.

In addition, the experiments yielded seven drugs that may be useful for treating faulty proteins linked to Parkinson’s disease, six for stroke and one for amyotrophic lateral sclerosis (ALS).

Scientists have worked for decades to develop treatments for Alzheimer’s by targeting genes rooted in the disease process but have had little success. That approach has led to several dead ends because many of those genes don’t fundamentally alter proteins at work in the brain. The new study takes a different approach, by focusing on proteins in the brain, and other tissues, whose function has been altered.

In this study, we used human samples and the latest technologies to better understand the biology of Alzheimer’s disease,” said principal investigator Carlos Cruchaga, the Reuben Morriss III Professor of Neurology and a professor of psychiatry. “Using Alzheimer’s disease samples, we’ve been able to identify new genes, druggable targets and FDA-approved compounds that interact with those targets to potentially slow or reverse the progress of Alzheimer’s.”

The scientists focused on protein levels in the brain, cerebrospinal fluid (CSF) and blood plasma of people with and without Alzheimer’s disease. Some of the proteins were made by genes previously linked to Alzheimer’s risk, while others were made by genes not previously connected to the disease. After identifying the proteins, the researchers compared their results to several databases of existing drugs that affect those proteins.

The new study, funded by the National Institute on Aging of the National Institutes of Health (NIH), is published in the journal Nature Neuroscience.

Source: https://source.wustl.edu/

Biomarker detects Alzheimer’s decades before symptoms appear

Two new studies, published in the journal The Lancet Neurology, are suggesting increasing levels of a particular brain protein, detected in blood and spinal fluid, could be the earliest sign of neurodegenerative diseases such as Alzheimer’s and Huntington’sNeurofilament light chain (NfL) is a protein that is released as a result of brain cell damage. It is one of the most promising early-stage biomarkers for a variety of neurodegenerative diseases, including Parkinson’s disease, ALS and multiple sclerosis.

It is commonly suspected that the neurodegeneration associated with many of these devastating diseases begins years, or even decades, before clinical symptoms finally appear. And on the back of many failed drug trials, researchers are beginning to believe that once symptoms eventually appear much of the neurological damage could be irreversible. So finding ways to catch these diseases at the earliest possible point will be vital in delivering effective treatments.

Huntington’s disease is a heritable neurodegenerative disease with no cure. Clinical symptoms can begin appearing at any age, however, generally the condition doesn’t become apparent until middle-age, and once symptoms do appear a gradual decline to death takes place over about 20 years. Researchers have homed in on a number of clues, both behavioral and physiological, to detect the earliest stages of the disease but a new study from an international team of researchers is suggesting NfL levels in cerebrospinal fluid (CSF) could detect Huntington’s neurodegeneration up to 24 years before the clinical onset of the disease.

Other studies have found that subtle cognitive, motor and neuropsychiatric impairments can appear 10-15 years before disease onset,” explains co-first author on the study, Rachael Scahill. “We suspect that initiating treatment even earlier, just before any changes begin in the brain, could be ideal, but there may be a complex trade-off between the benefits of slowing the disease at that point and any negative effects of long-term treatment.

The new study presents the most detailed investigation ever conducted into early-stage Huntington’s disease biomarkers in a young cohort of patients. The study recruited 64 subjects, all carrying the Huntington’s gene mutation, and all estimated to be an average of 24 years ahead of the disease onset. The cohort was subjected to a large assortment of tests, with the researchers searching for an early sign of the disease. Elevated CSF NfL levels, compared to a control group, turned out to be the most prominent early sign of the disease. The researchers suggest this is the earliest sign of neuronal damage related to Huntington’s disease ever detected, and offers scientists a new biomarker to use to recruit subjects for clinical trials testing new preventative treatments.

We have found what could be the earliest Huntington’s-related changes, in a measure which could be used to monitor and gauge effectiveness of future treatments in gene carriers without symptoms,” says co-first author Paul Zeun. In the Huntington’s study it was primarily NfL levels in spinal fluid that presented as the most effective early diagnostic biomarker of the disease. However, another new study examining NfL levels in relation to Alzheimer’s disease, is suggesting a more simple blood test could be useful in detecting NfL changes for that particular neurodegenerative disease.

A study published early in 2019 suggested increasing NfL levels in blood samples could detect Alzheimer’s disease around a decade before clinical symptoms appear. Yakeel Quiroz, from Harvard Medical School, wondered how early this biomarker could indicate the neurodegenerative disease.

We wanted to determine the earliest age at which plasma NfL levels could distinguish individuals at high risk of Alzheimer’s,” says Quiroz, co-first author on the study.

The researchers examined more than 1,000 subjects with a particular familial genetic mutation that makes them at a high risk of developing Alzheimer’s disease. The cohort was aged between eight and 75 years, and the results remarkably revealed increasing NfL levels could be detected at the early age of 22. The estimated median age of onset for mild cognitive impairment associated with this form of familial Alzheimer’s disease is 44, so the researchers say the biomarker could indicate the very earliest stage of neurodegeneration linked to the disease, 22 years before symptoms appear.

Source: https://newatlas.com/

Alzheimer’s May Be Caused By Dental Infection

In a new study scientists reveal yet another reason to keep up on dental hygiene. Bacteria that cause a common yet largely preventable gum infection may also play a role in Alzheimer’s disease. The discovery also offers hope for a treatment that could slow neurodegeneration.

There were many clues in the [features of Alzheimer’s disease] that an infection is at work,” said Casey Lynch, an entrepreneur and co-founder of Cortexyme, a biotech company headquartered at the Verily Life Sciences campus in South San Francisco, who led the new research. “Many of the genetic risk factors for Alzheimer’s are related to immune system function,” she added, which suggests “immune system dysfunction might put people more at risk.

Alzheimer’s disease, an irreversible and progressive brain disorder that leads to memory loss and diminished thinking skills, affects at least 5 million Americans. Clumps of a brain protein known as amyloid plaques are a hallmark sign of the disease. Billions of research dollars have gone towards finding a treatment that destroys these mind-robbing masses. But there’s still no cure.

Not enough people are asking what is upstream of the plaques … and [brain] inflammation,” said Lynch, who has a background in Alzheimer’s research and was frustrated by the string of failed therapies for the disease. Nearly six years ago, Lynch received a call from Stephen Dominy, a psychiatrist at the University of California, San Francisco, who had studied the link between HIV and dementia.

I think I’ve found a bacterial cause of Alzheimer’s,” Dominy, who co-founded Cortexyme with Lynch and now serves as the company’s Chief Scientific Officer, told her. Dominy had spent about 15 years searching for infections that might lead to Alzheimer’s until evidence for a bacterium known as P. gingivalis became “undeniable,” according to Lynch. P. gingivalis causes periodontitis, an infection that destroys the gums and can lead to tooth loss.

When the team examined the brains and cerebrospinal fluid of Alzheimer’s patients, they found DNA from the bacterium. They also discovered bacterial enzymes called gingipains that destroy brain cells were present, too. And when they watched P. gingivalis infections play out in mice, it triggered neurodegeneration in the hippocampus, a brain structure central to memory. It also led to Alzheimer’s hallmark amyloid beta plaque production and inflammation, the researchers discovered.

The scientists then designed and created a new molecule that blocks the gingipain enzymes. The antibiotic reduced the amount of bacteria in infected mice and stopped the formation of amyloid beta plaques while reducing inflammation, the team reports Wednesday in the journal Science Advances.

Source: https://www.discovermagazine.com/

Early-Stage Detection Of Alzheimer’s In The Blood

Two major studies with promising antibodies have recently failed – possibly because they have been administered too late. A new very early-detection test gives rise to hope. Using current techniques, Alzheimer’s disease, the most frequent cause of dementia, can only be detected once the typical plaques have formed in the brain. At this point, therapy seems no longer possible. However, the first changes caused by Alzheimer’s take place on the protein level up to 20 years sooner. A two-tier method developed at Ruhr-Universität Bochum (RUB) can help detect the disease at a much earlier stage. The researchers from Bochum published their report in the March 2019 edition of the journal “Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring”.

This has paved the way for early-stage therapy approaches, where the as yet inefficient drugs on which we had pinned our hopes may prove effective,” says Professor Klaus Gerwert from the Department of Biophysics at RUB.

In Alzheimer’s patients, the amyloid beta protein folds incorrectly due to pathological changes long before the first symptoms occur. A team of researchers headed by Klaus Gerwert successfully diagnosed this misfolding using a simple blood test; as a result, the disease can be detected approximately eight years before the first clinical symptoms occur. The test wasn’t suitable for clinical applications however: it did detect 71 per cent of Alzheimer’s cases in symptomless stages, but at the same time provided false positive diagnoses for nine per cent of the study participants. In order to increase the number of correctly identified Alzheimer’s cases and to reduce the number of false positive diagnoses, the researchers poured a lot of time and effort into optimising the test.

As a result, they have now introduced the two-tier diagnostic method. To this end, they use the original blood test to identify high-risk individuals. Subsequently, they add a dementia-specific biomarker, namely tau protein, to run further tests with those test participants whose Alzheimer’s diagnosis was positive in the first step. If both biomarkers show a positive result, there is a high likelihood of Alzheimer’s disease. “Through the combination of both analyses, 87 of 100 Alzheimer’s patients were correctly identified in our study,” summarises Klaus Gerwert. “And we reduced the number of false positive diagnoses in healthy subjects to 3 of 100. The second analysis is carried out in cerebrospinal fluid that is extracted from the spinal cord.

Now, new clinical studies with test participants in very early stages of the disease can be launched,” points out Gerwert. He is hoping that the existing therapeutic antibodies will still have an effect. “Recently, two major promising studies have failed, especially Crenezumab and Aducanumab – not least because it had probably already been too late by the time therapy was taken up. The new test opens up a new therapy window.”

Source: https://news.rub.de/