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Why it’s so hard to treat dementia



Not surprisingly, several companies have left this territory in recent years. Last week, pharmaceutical giant Pfizer announced that it will stop research on the development of drugs to treat Alzheimer's disease, after costly failed attempts in the last decade.
In recent years, some clinical trials involving potential drugs for dementia have had disappointing setbacks. In 2012, Pfizer and Johnson & Johnson suspended the development of the antibody drug bapineuzumab, after it failed late-stage trials to treat patients with mild to moderate Alzheimer's.
Despite last week's announcement, Pfizer's support of the UK Dementia Discovery Fund, an initiative involving the government, major pharmaceutical companies and Alzheimer's Research UK, may be where your money can achieve the greatest impact in this space.

The purpose of the fund is to promote investment in dementia research by financing early-stage drug development projects. And other pharmaceutical companies, such as Eli Lilly, Biogen and Novartis have continued to seek development of drugs against dementia with modest but promising success to date.

We are not prepared for the "silver tsunami" of older adults living with cancer [19659004] So, what makes dementia such a difficult condition to deal with drugs, and progress towards a treatment?

Why is dementia so difficult to treat?

Despite the large number of people affected worldwide, with an estimated 46.8 million people currently living with dementia, there is currently no cure. While current treatments handle symptoms (the last drug to obtain FDA approval was memantine, in 2003) they do not offer prospects for recovery.
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Part of the difficulty in finding treatments for dementia lies in the fact that it is not a single disease, but a complex health problem with more than 50 underlying causes. Dementia can best be considered a generic term that describes a variety of conditions that cause certain parts of the brain to progressively deteriorate.

Most of the pharmacological treatments currently under development have focused on the pathology of Alzheimer's disease, the most common form of dementia, which accounts for about 60 to 70% of all cases.
Finding a successful treatment for Alzheimer's faces two main obstacles: the first is that we still do not know enough about the underlying biology of the disease. For example, we do not know what exactly regulates the toxic buildup of amyloid-β plaques and tangles of tau in the brain that are found in Alzheimer's patients, which specific types of these are toxic or why the disease progresses at different rates. in different people.
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It does not help that the symptoms of Alzheimer's disease Alzheimer's develop gradually and slowly, and the diagnosis can only be made years after the brain has begun to undergo neurodegenerative changes. For starters, it is not uncommon for Alzheimer's to be present, as well as other forms of dementia.

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The second major obstacle to finding a treatment is that the drugs first need to cross the blood-brain barrier. The blood-brain barrier provides a defense against pathogens and toxins that cause diseases that may be present in our blood and, by design, exists to prevent the entry of foreign substances from the brain. The disadvantage is that it also prevents the vast majority of potential drug treatments from reaching the brain.

Promising steps in the right direction

Currently available drugs, such as those that block the actions of an enzyme that destroys an important chemical messenger in the brain for memory (acetylcholinesterase inhibitors) or blocks the effects toxic from another messenger, glutamate (memantine) temporarily manages the symptoms. But new treatments focus on slowing or reversing the disease process, addressing the underlying biology.

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One approach, called immunotherapy, involves the creation of antibodies that bind to abnormal developments in the brain (such as amyloid-β or tau), and mark them for destruction through a range of mechanisms. Immunotherapy is experiencing great interest and several clinical trials are currently underway, targeting both amyloid-β and tau.

Aducanumab, an antibody targeting amyloid-β, has shown promise in clinical trials and phase 3 trials are currently underway, as are several strategies based on tau. If one is successful, we would have a vaccine for Alzheimer's.
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It is estimated that only 0.1% of the antibodies circulating in the bloodstream enter the brain, this also includes the therapeutic antibodies currently used in clinical trials. One approach my team takes is to use ultrasound to temporarily open the blood-brain barrier, which increases the absorption of drugs or fragments of Alzheimer's antibodies.

We have been successful in mice, finding that ultrasound can eliminate groups of toxic tau proteins. and that the combination of ultrasound with an antibody fragment is more effective than any treatment just to eliminate tau and reduce the symptoms of Alzheimer's. The next challenge will be to translate this success into clinical trials in humans.

The task of developing drugs against dementia is not an easy task, and requires collaboration between government, industry and academia. In Australia, the National Dementia Network serves well for this purpose. Only through perseverance and continuous investment in research, one day we will receive a treatment for dementia.

Jürgen Götz is director of the Clem Jones Center for the Investigation of Dementia in Aging of the University of Queensland.


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