Discovering biomarkers for mixed dementia

Lead Investigator: Dr Devkee M. Vadukul 

Institution: Imperial College London

Grant type: Alzheimer's Society Dementia Research Leader Fellowship

Start date: March 2025

Duration: 60 months

Amount: £549,999.00

Project summary:

For a person living with dementia, one of the biggest challenges is receiving a timely and accurate diagnosis.  

Currently, around 50% of people diagnosed with dementia have mixed dementia, meaning their dementia involves several types of disease dementia, such as Alzheimer's disease, Parkinson's disease, or frontotemporal dementia.

However, diagnosing mixed dementia accurately is difficult because it mostly relies on observing symptoms, rather than clear biomarkers – biological ‘red flags’ for diseases that can be tracked and measured. 

Dr Vadukul aims to identify and validate specific biomarkers called mixed-protein clumps as new biomarkers. This could help doctors to diagnose mixed dementia earlier, more accurately, and more reliably than current methods.

Project background:

Dementia is typically diagnosed using memory tests, cognitive assessments, and biomarkers. 

Biomarkers are biological ‘red flags’ for diseases and can be tracked and measured. They are often clumps of abnormal proteins that build up in the brain. The build up of different proteins are associated with the different diseases that cause dementia e.g. Alzheimer's disease is linked with the amyloid-beta and tau, Parkinson’s disease with α-synuclein, and frontotemporal dementia with TDP-43.

Studies of brain tissue after death have found that up to 50% of people diagnosed with a diagnosis of a single type of dementia actually have mixed-protein clumps (also known as hetero-aggregates), containing multiple proteins. This indicates that many dementia cases are actually "mixed" at a biological level. Currently, these mixed-protein clumps cannot be reliably detected with existing tests, highlighting the urgent need for new, accurate biomarkers.

What does this project project involve?

Dr Vadukul’s research will study mixed-protein clumps carefully and develop ways to detect them. This project involves:

1. Identifying mixed protein clumps in dementia patients:
   Dr Vadukul will closely analyse brain samples from patients diagnosed with Alzheimer's, Parkinson's, and frontotemporal dementia. She will specifically look for mixtures of tau, α-synuclein, and TDP-43 proteins, which commonly form mixed-protein clumps.
2. Understanding how these clumps form:
   To understand the biology behind mixed dementia, Dr Vadukul and her team will recreate these protein clumps in the laboratory. By combining different proteins under controlled conditions, Dr Vadukul can carefully observe how these mixed-protein clumps form, which will help uncover the reasons behind their appearance in the brain.
3. Studying Their Impact on Brain Cells:
   Dr Vadukul and her team will investigate how these mixed clumps affect the health of human brain cells grown in the lab. The goal is to find out if these clumps cause inflammation or cell death, and exactly how they damage the brain. Special attention will be given to whether certain inflammatory processes contribute to the harmful effects of these protein clumps.
4. Creating New Tools for Diagnosis:
   Finally, Dr Vadukul will develop specialised DNA-based molecules called aptamer probes. These probes will specifically attach to mixed-protein clumps, potentially allowing doctors to detect them early and accurately, using straightforward diagnostic tests.

How will this project help people with dementia?

This research could be the first step towards improving the accuracy of mixed dementia diagnoses if Dr Vadukul’s research shows that mixed-protein clumps can be a reliable biomarker. 

Earlier and more accurate diagnosis means that the people living with the diagnosis and their loved ones can have more time to plan and consider options for care and support.