Early days for Alzheimer's test

A simple blood test may soon be able to “predict Alzheimer's disease up to 10 years before symptoms appear”, says The Daily Telegraph . The newspaper says researchers have discovered that a rise in levels of a protein called clusterin may be an early sign of the disease.

The observational and laboratory studies that lie behind this report have been well conducted and reported, and its authors have found clusterin levels are linked to cognitive decline, the severity of disease in people with Alzheimer’s and the rate of clinical progression of Alzheimer’s disease. However, the researchers do not suggest that this may be used to diagnose disease, at least not yet. In fact they say that their study does not support the clinical use of clusterin levels as a standalone biomarker for Alzheimer’s disease. These are interesting findings, but early ones that will lead to more research about protein markers of this disease rather than directly to a clinical test.

Where did the story come from?

The study was carried out by researchers from King’s College London and a number of medical and academic institutions across the world. The study was funded by the European Union and authors received funding from the Alzheimer’s Research Trust, the UK National Institute for Health Research, the Biomedical Research Centre for Mental Health, the Bupa Foundation and the Alzheimer’s Society. The research was published in the peer-reviewed medical journal Archives of General Psychiatry.

What kind of research was this?

This study consisted of several different phases of research that together aimed to explore how the development of Alzheimer’s disease may be associated with changes in the proteins found in the blood. It is hoped that any associated changes in the protein composition of the blood could therefore form the basis of future blood tests for detecting early Alzheimer’s disease.

Results of MRI and PET scan images were used to determine the pathology of disease in the brain: atrophy (wasting) in the medial temporal lobe of the brain (specifically hippocampus and entorhinal cortex) is associated with changes in Alzheimer’s disease, and so observations of smaller volumes in this part of the brain might provide indications of early Alzheimer’s. The researchers also made distinctions between slowly and rapidly developing disease in a case group of people with Alzheimer’s disease or cognitive impairment. This allowed the researchers to go beyond a simple two-way distinction between cases and controls subjects and to also investigate whether particular proteins could be markers for the severity of disease.

The study first focused on profiling those proteins that may be associated with atrophy in specific parts of the brain in people with Alzheimer’s disease. To validate the found associations the next study phase determined whether the protein clusterin was associated with brain atrophy in another sample of individuals. Levels of these biomarker proteins were also tested for associations with cognitive symptoms (as measured using a recognised test of cognitive function)

What did the research involve?

The researchers called the early parts of their study the ‘discovery studies’; here they tried to identify which proteins could be useful in diagnosing Alzheimer’s disease. In this cross-sectional part of the study, the researchers analysed blood proteins in a total of 95 people with mild cognitive impairment or established Alzheimer’s disease. They also determined protein profiles for those with rapidly progressing Alzheimer’s and those with a less aggressive form of the disease.

The second part of the study was the ‘validation’ phase, testing the associations of the discovery phase. A sample of 689 subjects was followed for a year, with the researchers assessing whether they could use the proteins they had previously identified to detect presence or absence of disease, and also whether this was rapidly progressing or progressing less slowly. Rapidly declining patients were those with a fall of two points or more on the mini-mental state examination (a recognised, validated test of cognition) in a one-year period.

All of the participants involved in this study were also enrolled in other studies, either a cohort study funded by the King’s College Alzheimer Research Trust (KCL-ART), or the AddNeuroMed study. These studies, which enrolled people with Alzheimer’s disease, Mild Cognitive Impairment (MCI) and healthy adults, allowed the researchers access to a range of further details on the participants, plus blood samples taken at the beginning of each of these studies (up to 10 years ago). The researchers then extracted plasma proteins from blood samples provided by the study participants and used regression (a statistical technique) to determine which proteins were associated with the scan-determined volume of the hippocampus in people with MCI and with Alzheimer’s disease, and specifically with an accelerated rate of cognitive decline.

In a third part of the study the researchers had data available on 60 healthy people who provided blood samples and then had brain scans 10 years later. They used this group to assess the link between clusterin and brain atrophy in people without Alzheimer’s disease.

What were the basic results?

The researchers identified clusterin as being associated with brain pathology, the severity of disease and how rapidly the disease progressed. They found that there was a trend towards an association between clusterin concentration and ‘atrophy in the ERC region of the brain’ in patient’s with combined MCI and Alzheimer’s disease. However, this was highly significant in people with Alzheimer’s disease only. Clusterin levels were also strongly associated with scores on a scale measuring disease severity in people with MCI and Alzheimer’s disease.

How did the researchers interpret the results?

Of all the proteins assessed, only clusterin was associated with the ‘hippocampal atrophy’ in Alzheimer’s disease, patients with MCI and the fast progressing, or more aggressive, Alzheimer’s disease. The researchers say that their results demonstrate an important role of clusterin in Alzheimer’s disease.

Conclusion

This is a well-reported observational study that has identified a particular protein in the blood that was able to distinguish between different degrees of brain atrophy in people with Alzheimer’s disease and mild cognitive impairment, plus between different disease types (aggressive or not).

In the third phase of this study, using a separate sample of 60 healthy people, the researchers assessed whether there was an association between the concentrations of clusterin in the blood and evidence of brain atrophy 10 years later. With this result in particular, it is important to stress the difference between finding a cause and finding an association, as it is the one that the newspapers have given the most emphasis to: the participants had not had brain scans performed at the time of the original blood test and therefore it is impossible to tell if there truly were any advances in atrophy over this period.

For all sub-studies, blood samples were only taken at baseline, although data on symptoms of cognitive decline were available at regular intervals following the reporting schedules of the two studies. The assumption that levels of plasma proteins remain constant during the course of the studies is an important one that may not be true. The researchers took into account some factors that may be associated with these measures, including age, gender and duration of disease. It is a strength of the study to include these important variables in this way, although it is still difficult to control for all possible confounders, particularly if relying on data from studies that have already started.

Overall, it may be a leap to say that this protein could be used as a diagnostic tool for Alzheimer’s disease. The researchers themselves specifically say that “these findings do not support the clinical utility of plasma clusterin concentration as a standalone biomarker for AD…” suggesting that more research is needed to see how these findings can apply to practice. However, the study does show the role that clusterin, and perhaps other plasma proteins, have in the Alzheimer’s process.