Finding biological markers that can help to diagnose and monitor Alzheimer's disease

Research project: Plasma metabolites as Alzheimer's Disease (AD) biomarkers: Utilising metabolite levels for AD classification and prediction and understanding how genomic, transcriptomic, proteomic and imaging variation is associated with metabolic changes

Lead applicant: Dr Petroula Proitsi
Institution: Institute of Psychiatry, King's College London
Grant type: Fellowship
Amount awarded: £199,777
Duration: 3 years
Start date: October 2012
End date: December 2015

What was the project, and what did the researchers do?

It is hard to diagnose and track Alzheimer's disease, because we don't have enough of an understanding about the biological changes that occur as part of the disease process.

Biomarkers are biological signals that can be easily measured and can be used as indicators of disease presence and stage.  Specific changes that that can be measured within the blood that accurately identify Alzheimer's disease would be extremely useful tools to help to monitor a person's health throughout their journey with Alzheimer's disease.

Dr Proitsi analysed chemicals in blood samples from participants for patterns that are different in people with dementia. She compared these to clinical information and brain scans. 

What were the key results, and how will this help in the fight against dementia? 

The first experiment involved comparing samples from people with either Alzheimer's disease, mild cognitive impairment or no disease (~40 people per group). This showed that there were lower levels of certain cholesterol products in people with Alzheimer's. As there appeared to be no effect on synthesis of cholesterol, it is likely to be due to a difference in how the cholesterol is used by the body in people with dementia.

Using this information, it was possible to find a pattern of the levels of 24 molecules that predicted, with more than 70% accuracy, both disease progression and brain shrinkage in a larger group of 150 patients. This was the first such study to link a range of fat (lipid) molecules in the blood with brain shrinkage. In addition the DNA sequences of people in the study were analysed, and markers were identified that appear to show variation in how the body uses fats in people with Alzheimer's disease. 

There are therefore two directions in which the results of this research could point.  One is practical: if a blood test can help to diagnose people earlier and more accurately, this would be a major diagnostic advance. It could directly help people to gain access to treatments, support and services that will help them to live well with dementia. It may also allow more tailored support. In addition, such tests will become more critical as drugs become available that can actively slow disease progression.

The second research direction is the longer term aim to improve our understanding of the biology behind the disease.  Understanding what changes occur in the brain, and which signals then appear in the blood, is key to increasing our understanding of the development of Alzheimer's disease, which will help in the search for new treatments. Knowing which blood molecules or DNA markers were changed in people with or at risk of Alzheimer's will allow future projects to carry out more detailed studies as to what role they play, and whether they are avenues to better diagnosis or treatment.

What happened next? Future work and additional grants

Dr Proitsi has been awarded one of UCL's prestigious Springboard Population Science Fellowships, which are given to the highest calibre early career researchers internationally. She also holds a Senior Fellowship from Alzheimer's Research UK that seeks to take the findings described above further.

How were people told about the results? 

Publications:

Østergaard SD et al. Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study. PLoS Med. 2015 Jun 16;12(6):e1001841. PubMed PMID: 26079503. 

Velayudhan L et al.  Pattern of Smell Identification Impairment in Alzheimer's Disease. J Alzheimers Dis. 2015 May 30;46(2):381--‐7. PubMed PMID: 25757648. 

Proitsi P et al. Plasma lipidomics analysis finds long chain cholesteryl esters to be associated with Alzheimer's disease. Transl Psychiatry. 2015 Jan 13;5:e494. PubMed PMID: 25585166. 7

Proitsi P et al. Genetic predisposition to increased blood cholesterol and triglyceride lipid levels and risk of Alzheimer disease: a Mendelian randomization analysis. PLoS Med. 2014 Sep 16;11(9):e1001713. PubMed PMID: 25226301. 

Proitsi P et al. Alleles that increase risk for type 2 diabetes mellitus are not associated with increased risk for Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2883.e3--‐2883.e10. PubMed PMID: 25150574. 

Conferences

This work was presented at four conferences.

Other dissemination activities

Dr Proitsi's work was covered on Alzheimer's Society's website as part of our 'Dementia Research Leaders news' section and in an issue of our research magazine, Care and cure.

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Further reading