Detecting seeded protein aggregation in Alzheimer's disease
Research type
Research Study
Full title
Detecting seeded protein aggregation in serum samples from patients with Alzheimer's disease versus controls
IRAS ID
227666
Contact name
Usha Menon
Contact email
Sponsor organisation
University College London
Clinicaltrials.gov Identifier
Z6364106/2017/07/20, UCL Data Protection Registration
Duration of Study in the UK
1 years, 4 months, 25 days
Research summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects over 46 million worldwide and is the most common cause of dementia. It affects 1 in 20 over-65 year olds and 1 in 5 over the age of 80. With an increasingly aging population the number of people affected will double by 2030, reaching more than 115 million by 2050. An unmet need in the diagnosis of AD is effective testing. Currently there is no reliable pre-symptomatic test for AD with existing tests often being invasive and measuring only late-stage manifestations of the disease. Thus, there is a great need both for clinical diagnosis and drug discovery to be able to measure fundamental early disease processes.
There is a substantial body of evidence that the clinical progression of a range of age-related brain disorders including AD is caused by a spread in specific protein aggregation pathology. Examination of brain tissue from patients diagnosed with such diseases reveals abnormal deposits of protein in, or around cells, with the proteins becoming misformed and sticking together forming plaques, tangles or inclusion bodies. These deposits are not inert and may be the source yield of soluble fragments (“seeds”) that break off and spread to neighbouring cells.
Cambridge University has developed a novel microfluidic technique (patent application EP2962114-A1) that detects the presence of such protein seeds within biological samples. Two proteins are involved in the progression of AD: Amyloid beta (Aβ) which forms the “plaques” and Tau that creates “tangles” within neurons. It is proposed that soluble aggregates of polypeptides such as Aβ or Tau can diffuse and stimulate similar aggregation processes around the brain.
The aim of this project is to detect seeded protein aggregation in serum samples from patients with AD versus age-matched controls. For this, longitudinal pre-diagnosis serum samples collected from volunteers during the course of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) trial who were later diagnosed with AD will be used. Controls (no record of AD diagnosis or similar neurological diseases) will also be selected for comparison. Clear distinction between AD and non-AD samples will mean that the assay has the potential to be used as the first diagnostic test that directly measures pathological markers (seeding activity) of the disease in human serum.
Lay summary of study results: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Currently there is no reliable pre-symptomatic test for AD with existing tests often being invasive and measuring only late-stage manifestations of the disease. The progression of neurodegenerative diseases such as Alzheimer’s may be driven by a process of seeded aggregation. In this project it was proposed that soluble aggregates of polypeptides, such as the amyloid beta peptide, can diffuse and stimulate similar aggregation processes around the brain. Our collaborator at Cambridge University had developed in an animal model a novel microfluidic technique that detected the presence of such protein seeds within biological samples from diseased but not control tissues. The goal of this project was to investigate whether this could be validated using human serum samples from Alzheimer's patients and heathy controls. This project encountered several delays related to troubleshooting required for assay optimisation, staff limitations and also the pandemic. The collaborator explored various elements of the assay optimisation (including titration of amyloid beta concentrations) in an effort to achieve reproducible results and improve the signal-noise ratio. The experiments so far have been done on a small number of serum samples in order to avoid wasting valuable material while still optimising the assay parameters. Overall, the samples used so far have provided encouraging data, with serum from Alzheimer's cases being significantly different from background, with more amyloid beta aggregation compared to the age-matched controls. However more testing on the rest of the samples is required before our collaborator can conclude if this assay can be used to test for alpha beta aggregation as a marker for Alzheimer’s disease in serum samples. As this project has taken more time than anticipated it has been decided that UCL will submit an end of study report under the current application. Our collaborator will then continue the project depending on the availability of staff and resources available to carry on the work. Our collaborator has submitted the project at Cambridge University Research Ethics Committee and approval will be obtained prior to the continuation of the work.REC name
South Central - Hampshire A Research Ethics Committee
REC reference
17/SC/0375
Date of REC Opinion
26 Jul 2017
REC opinion
Favourable Opinion