Detecting early signs of Alzheimer’s disease through a blood test

Disease and treatment 11. apr 2024 3 min Postdoctoral Fellow Kristian Juul-Madsen, Professor Thomas Vorup-Jensen Written by Kristian Sjøgren

Researchers have developed a method to detect whether a person has early signs of Alzheimer’s disease by using a blood test, enabling earlier treatment. The researchers also now have a deeper understanding of the mechanisms that protect the brain against Alzheimer’s and how to intervene early.

Despite studying people with Alzheimer’s for many years, researchers still do not completely understand this neurodegenerative disease – and how to treat these people optimally.

A blood test method has been developed for identifying people with early signs of Alzheimer’s, and although more needs to be done to determine how to treat them, the new study also shows some potential for new methods of treatment.

The researchers identified a specific receptor that appears to strengthen the brain’s defences against accumulating the harmful proteins that lead people to develop Alzheimer’s.

“Our study has wide-ranging perspectives for identifying people developing Alzheimer’s and for developing new drugs to treat them,” explains a researcher involved in the study, Kristian Juul-Madsen, Postdoctoral Fellow, Department of Biomedicine, Aarhus University, Denmark.

The research, which was carried out in collaboration with Professor Thomas Vorup-Jensen and other researchers, has been published in Nature Communications.

A blood test to identify Alzheimer’s

How can the early signs of Alzheimer’s be identified through a blood test?

A protein called amyloid-beta aggregates in the brain in Alzheimer’s and leads to neurodegeneration. Amyloid-beta is also present in the blood.

The method can identify when amyloid-beta aggregates in the blood by using an antibody that can recognise and bind to the aggregates of amyloid-beta.

The system is based on nanoparticle tracking analysis and quantum dots conjugated with the detecting antibodies that the researchers can track with a camera and a microscope.

The researchers monitor how rapidly the quantum dots move in the bloodstream, thereby indicating how aggregated the amyloid-beta is. The slower amyloid-beta moves, the larger the aggregates are and the more likely that this indicates Alzheimer’s.

“This enables us to identify large aggregates of amyloid-beta in a blood sample, thereby indicating whether someone has early signs of developing Alzheimer’s, even before it can be identified with a PET scan,” says Kristian Juul-Madsen.

Validating the method by identifying people developing Alzheimer’s

The researchers validated their method in a trial with two groups of participants: one group with no signs of Alzheimer’s and the other with mild cognitive impairment, which may indicate Alzheimer’s but also other diseases and conditions.

By analysing the blood samples, the researchers ruled out that any control participants had early signs of Alzheimer’s. Some participants with mild cognitive impairment had early signs of Alzheimer’s and others did not.

Thomas Vorup-Jensen says that examining the accumulation of amyloid-beta aggregates in the brain currently requires positron emission tomography, but this only helps to diagnose Alzheimer’s late in the disease trajectory.

“Our method can find signs of Alzheimer’s much earlier, which also enables earlier intervention,” he adds.

Immune system is important

The second part of the research focused on the interaction between amyloid-beta aggregates in the blood and in the brain and the role of the immune system.

This revealed that people with high levels of amyloid-beta aggregates also had high levels of non-classical monocytes in the blood, which have a key role in maintaining people’s blood vessel walls. People with Alzheimer’s often have especially thin vessel walls in the blood–brain barrier.

Researchers have long suspected that the blood vessels and the immune system have important roles in developing Alzheimer’s, and non-classical monocytes may be the connecting link.

“Recruitment of these monocytes, like the accumulation of amyloid-beta aggregates, is a sign of developing Alzheimer’s,” says Thomas Vorup-Jensen.

Receptor keeps Alzheimer’s in check

The researchers also examined the non-classical monocytes and found that this type of immune cell has large quantities of complement receptor 4 on the surface, and this receptor strongly binds amyloid-beta aggregates.

Overall, this indicates that the non-classical monocytes bind to the vessel wall through aggregates of amyloid-beta, which are themselves attached to the vessel wall.

“Non-classical monocytes are upregulated in response to increasing aggregation of amyloid-beta in the blood, and this is therefore a beneficial process. When this system does not function properly and the binding fails between complement receptor 4 on the surface of the monocytes and the amyloid-beta aggregates, the prognosis becomes worse. This makes complement receptor 4 a potential drug target, because strengthening it could neutralise amyloid-beta,” explains Kristian Juul-Madsen.

Breaking down amyloid-beta aggregates in the brain

However, the most crucial aspect of Alzheimer’s affects the brain and not the blood. The researchers therefore also investigated how activating complement receptor 4 on the surface of the non-classical monocytes affects the processes in the brain.

This revealed that activating complement receptor 4 can increase the activation of the microglia cells inside the brain, and these break down amyloid-beta aggregates.

The study thereby investigated many major components of the progression of Alzheimer’s, and the researchers now understand much better how amyloid-beta aggregates and how the immune system and the brain interact to protect against Alzheimer’s. This also points to previously unknown conditions in which the body may be out of balance and the brain cells start to be damaged.

“This suggests several approaches to treating people with Alzheimer’s. We must find a balanced way of intervening, so that we both activate the body’s alarm and repair system without activating the alarm system excessively and leading to inflammation instead. Our study identifies some potential targets for intervention that we hope can be used to treat people with Alzheimer’s, since current treatment is not optimal,” concludes Thomas Vorup-Jensen.

Amyloid-β aggregates activate peripheral monocytes in mild cognitive impairment” has been published in Nature Communications. The study was funded by the Aarhus University Research Fund, the Danish Alzheimer Association, the Lundbeck Foundation, Independent Research Fund Denmark, the Danish National Research Foundation, the Intramural Research Program of the United States National Institutes of Health, the United States National Institute of Biomedical Imaging and Bioengineering and the Novo Nordisk Foundation.

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