Crossing the brain’s protective barrier – the next generation of dementia treatments

Why is the blood-brain barrier an issue?

The blood-brain barrier is a natural roadblock of tightly bound cells. It stops toxins and pathogens like bacteria and viruses from reaching the brain. 

It also stops helpful drugs from entering, including those we want to cross over from blood to brain to target amyloid-beta plaques or tau tangles - two abnormal protein build-ups associated with Alzheimer's disease.

The larger the drug, the less likely it is to be able to cross the blood-brain barrier. Antibodies are some of the latest treatments that could slow or stop the progression of Alzheimer's disease. However, antibodies, which are a type of protein produced by the body’s immune system to fight against disease, are some of the largest drugs. They can be up to 150 times larger than the chemical that makes up paracetamol.

So, while antibody drugs can cross the blood-brain barrier, it’s a slow process. Treatments need to use larger amounts of antibody so that enough reaches the brain to have an effect.

Researchers are designing dementia treatments to more easily cross the blood-brain barrier. 

Using existing receptors to reach the brain

Like antibodies, sugars, vitamins and minerals are too large to quickly cross the blood-brain barrier. But, they are essential for a healthy brain. Specialised proteins called 'receptors' coat the cells that make up the blood-brain barrier.

There is no “one-fits-all” approach for receptors. In fact, there are so many different types that researchers are still finding new ones. One receptor shuttles sugars, another shuttles iron, and still others shuttle vitamins.

Researchers are exploring ways to use receptors to transport Alzheimer's disease antibody treatments across the blood-brain barrier by using a technology called as “bispecific” antibodies. An antibody usually binds to one target. A "bispecific antibody" can bind to two different targets. For dementia treatments, one end of the antibody targets amyloid-beta plaques. The other binds to a receptor that will shuttle the antibody across the blood-brain barrier. 

Bispecific antibodies have already been successful in immunotherapy treatments. For example, antibodies can bind together cancerous cells and immune cells, so causing the immune system to attack and kill the cancer.

Trontinemab shows promise in clinical trials

Trontinemab binds to amyloid beta plaques and crosses the barrier through the receptor that shuttles iron into the brain. By attaching to this receptor, trontinemab is actively transported across the blood-brain barrier. Researchers have named this Brainshuttleᵀᴹ technology.

In early clinical trials, trontinemab cleared amyloid beta plaques in nine out of ten people within 28 weeks. This means visible markers of Alzheimer’s disease were removed.

Brainshuttleᵀᴹ technology also means antibody doses can be kept low as more antibody reaches the brain. Researchers think this will help with some of the side effects seen with earlier treatments, like lecanemab and donanemab.

Trontinemab is currently undergoing the last stages of clinical trials. These trials recruit large numbers of patients to make sure treatments are safe and effective for a wide range of different people.  

The two trials are recruiting people with mild cognitive impairment or mild dementia because of Alzheimer’s disease. Over 1,600 people are expected to be recruited across 18 different countries.

The first participants are being pre-screened to enter the trial. We are proud that some of these people are being pre-screened by Alzheimer's Society Dementia Research Nurses. 

Searching for longer lasting treatments

The iron transporting receptor is not the only option being explored by researchers. Other receptors have shown promise in early studies, either in human cells or in animals.

Some organs, like the liver, send signals to the brain by releasing hormones. These hormones are often too big to pass through the blood–brain barrier, so they, too, rely on receptors.

The ‘Grabody B platform’ works by adding a small protein to an antibody drug so the treatment can attach to one of these receptors and reach the brain. Because this added protein can be paired with many different antibodies, the approach could help a wide range of treatments reach the brain. A Parkinson’s antibody treatment using Grabody B is already in early clinical trials, and researchers are now investigating whether the same method might work for Alzheimer’s treatments as well.

Using different receptors may change how fast or slow drugs cross the blood-brain barrier. Other research groups are targeting part of the receptor that transports large amino acids. This receptor transports drugs more slowly than the iron transporting receptor. But, early evidence also suggests the transported antibodies might stay in the brain longer. This could help researchers fine tune how long treatments stay in the brain so they can be most effective.

And that’s not all, research is ongoing to find more receptors. Some studies are using artificial intelligence to predict the best receptors to study.