Alzheimer’s Expert: What Does the Future of Dementia Diagnosis Look Like?
Professor Henrik Zetterberg shares his perspectives and research on developing next-generation diagnostics for dementia.
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Dementia is an umbrella term that refers to loss of memory, language, problem-solving and other cognitive abilities caused by physical changes that occur in the brain.
Dementia sadly reshapes an individual’s life and often that of their loved ones. Despite decades of research, efficacious approaches to diagnose and treat dementia before it has progressed are limited. It therefore presents as one of the most pressing health challenges of our generation; according to Alzheimer’s Disease International, global cases are projected to reach 78 million by 2030.
While several types of dementia exist – such as vascular dementia, frontotemporal dementia and Lewy body dementia – the most common form is Alzheimer’s disease (AD), which accounts for 60–80% of cases.
A hallmark of AD is the accumulation of abnormal amyloid beta (Aβ) proteins in the brain, which form plaques and disrupt healthy neuronal function. The amyloid cascade hypothesis of AD positions this process as central to the disease’s pathogenesis. It has been a primary research focus of the field for decades, leading to two recent milestone moments: the US Food and Drug Administration’s approval of lecanemab in July 2023 and donanemab in July 2024. Both are anti-amyloid monoclonal antibodies that are designed for patients in the early stages of AD.
The amyloid cascade has faced scrutiny over the years, largely due to the failure of many other amyloid-targeting drugs that came before lecanemab and donanemab. As such, it’s now more widely accepted that multiple factors – not just the amyloid cascade – likely contribute to the development and progression of AD. But what are those factors?
Professor Henrik Zetterberg is a leading expert in the development of biomarkers for AD and other brain disorders at the UK Dementia Research Institute, University College London. Over the last 15 years, Zetterberg has utilized his background in molecular biology and medicine to identify molecular changes that occur in AD pathogenesis and explore how these changes might be harnessed to help diagnose the disease in its early stages.
Recently, he began combining proteomics methods with quantitative dried blood spot sampling and quantitative dried plasma sampling. His lab is conducting ongoing studies using cards that allow blood cells to be separated during sampling, providing a precise and quantitative volume, to create a new approach for measuring AD biomarkers remotely. This method, he explains, could help improve the detection and speed of diagnosis in AD, as well as support diagnostic workflows in low-income countries.
Technology Networks interviewed Prof. Zetterberg for World Alzheimer’s Day 2024 to learn more about his work and outlook on the future of AD and dementia research.
Henrik Zetterberg, PhD (HZ): Biomarkers are extremely important across neurodegenerative dementias and that is because of the human brain. These neurodegenerative diseases, and their pathologies, start to accumulate around 15–20 years before we see clinically recognizable symptoms. That is not because the brain is healthy and resists these pathologies over time, but it's simply the brain's enormous and fascinating capacity to compensate for network disturbances that occur when protein clumps are building up in the brain.
The brain can resist a lot but eventually, the symptoms arise and by that point the brain is quite sick. The neural networks are starting to become impaired or injured beyond their capacity to compensate. We want, of course, to identify the diseases before that stage.
This is where biomarkers are important. Simplified testing for biomarkers will also be crucial because then one could do this type of testing in people who are not in the hospital system. Further, people could start preparing their physician with a blood sample and some remote cognitive testing, for example, over the iPhone. This would provide a lot of information to the physician when they eventually seek advice for vague symptoms that might be very hard to differentiate between a normal situation and a pathological one.
Taken from Technology Networks.
Gustav Ceder (GC): How does remote microsampling work in the context of Alzheimer’s diagnostics?
HZ: If you do a finger prick test on yourself and put this blood on a collection device – preferably so that you get dried plasma-like material – then you can measure all of the important blood biomarkers for AD. If you use this with a multiplexed, ultra-sensitive technique, then you can do it with one single dried drop.
These measures correlate extremely well with standard venous blood-based measurements. So, we think that this will work on a scale and the biomarkers seem to be stable in this environment at room temperature for at least six months.
This work can help us to democratize AD diagnostics – one could now send out these cards to rural or remote areas where there is no laboratory nearby and trust the postal service to get the samples to the lab.
Taken from Technology Networks.
MC: On World Alzheimer’s Day 2024, what is one thing that you would like the public to know about the disease or research field?
HZ: I think that we should celebrate some success on this day. I'm thinking about the anti-amyloid antibodies that now seem to do something clinically meaningful to this disease for patients.
There are still a lot of struggles that we must go through to make these drugs available, not least in Europe, but we are also seeing this drug becoming clinically implemented in the US, Japan, China and other parts of the world. We will learn a lot from that [implementation]. But yes, I think it's time to celebrate a little bit.
Taken from Technology Networks.
MC: Looking to the future, short- and long-term, what do you think should be the number one priority in dementia and brain disorders research? Do you see innovations like microsampling playing a role in addressing those needs?
HZ: Short-term, I think we should rapidly develop a solid and well-validated blood-based algorithm to help diagnose early AD, to meet the need for rapid diagnostics to prescribe and monitor treatments in the long run.
I also think we should try to develop a blood-based biomarker for dangerous amyloid-related imaging abnormalities (ARIA). This is a possible side effect of the anti-amyloid antibodies that have caused the most problems when this class of drugs has undergone regulatory evaluation for approval. If we could establish this using dried plasma or blood spots, then we have made it very easy for the patients.
Long-term, I think we need to develop better biomarker panels for non-Alzheimer’s neurodegenerative dementias. We have promising pilot results on alpha-synuclein and TDP-43 in vesicles that are present in the bloodstream, but there is still a need to evaluate this further and establish exactly how to measure these pathologies. We also need better biomarkers for neuroinflammation that work in blood and better blood biomarkers for cerebrovascular dysfunction and disease.
Taken from Technology Networks.
The above content is a transcription of Professor Henrik Zetterberg’s video interview. It has been edited for clarity and flow to ensure a better reading experience. While every effort has been made to preserve the original content and meaning, some minor adjustments have been made to improve readability.
Professor Henrik Zetterberg was speaking to Gustav Ceder, Science Communicator, and Molly Coddington, Senior Science Writer and News Team Lead for Technology Networks.
