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From Medscape Medical News

Amyloid Chaperone Protein Linked to Alzheimer's Disease Severity and Progression

Megan Brooks

Authors and Disclosures

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July 7, 2010 — Higher plasma concentrations of clusterin are associated with the development, severity, and progression of Alzheimer's disease (AD), according to a study published in the July issue of Archives of General Psychiatry.

Clusterin belongs to a family of extracellular chaperone proteins that regulate the formation and removal of amyloid.

"Our finding suggests plasma clusterin might be increased very early in the disease process and years before the disease becomes clinically manifest," lead researcher Simon Lovestone, PhD, of King's College London and the Institute of Psychiatry, United Kingdom, told Medscape Medical News.

"If this is indeed the case then plasma clusterin might be used both to identify people who might be candidates for drug trials of agents designed to slow and prevent the condition and then to direct people to these therapies when available," he added.

Discovery and Validation Studies

Dr. Lovestone's team used a combined mass spectrometry–based proteomic and structural neuroimaging approach to identify plasma proteins associated with AD. Subjects included patients with AD, mild cognitive impairment (MCI), and healthy controls from the multicenter European AddNeuroMed study and the Baltimore Longitudinal Study of Aging.

In 2 discovery-phase studies (including 27 patients with AD, 17 with MCI, and 51 healthy controls), only clusterin was associated both with hippocampal atrophy in patients with AD and MCI and with rapidly progressing AD, the researchers found.

A larger validation study in 689 patients (including 464 with AD, 115 with MCI, and 110 controls) confirmed highly significant associations of plasma clusterin levels with atrophy of the entorhinal cortex (P = .001), a region next to the medial temporal lobe important in memory and a site of early AD, and with Mini-Mental State Examination (MMSE) score and rate of progression in AD (P < .001 for both).

Antecedent Marker of Disease?

Increased clusterin levels were also associated with a significantly greater risk for subsequent accelerated cognitive decline in patients with AD and in healthy controls, with the subsequent appearance of fibrillar amyloid-β deposits in the entorhinal cortex. This latter finding, note the researchers, suggests that clusterin is elevated "very early, possibly as an etiopathological event, and is not simply a reaction to other pathology in AD."

The researchers also measured clusterin messenger RNA (mRNA) levels in blood cells from 182 AD patients, 179 with MCI and 207 controls. Pairwise comparisons revealed significantly higher clusterin gene expression in AD patients than in MCI and control subjects (P = .008 and P < .001, respectively).

However, there was no significant association between clusterin mRNA in blood cells and plasma concentration of clusterin protein or between plasma mRNA levels and either MMSE score or rate of decline in MMSE score within groups or with atrophy on neuroimaging.

There were also no significant effects of the 7 clusterin gene polymorphisms on either clusterin mRNA expression in blood cells or plasma concentration of clusterin.

In a transgenic mouse model of AD, the researchers observed increased plasma clusterin, age-dependent increase in brain clusterin, and amyloid and clusterin colocalization in plaques.

Findings Potentially "Revolutionary"

Commenting on the study for Medscape Medical News, John Breitner, MD, MPH, professor of geriatric psychiatry at the University of Washington, Seattle, who was not involved in the research, said, "What is extremely encouraging about this research is that this is a marker that can be obtained easily from blood. If the finding can be reproduced, this would be revolutionary."

Dr. Lovestone and colleagues make the point in their article that the current findings "do not support the clinical utility of plasma clusterin concentration as a stand-alone biomarker for Alzheimer's disease." They do, however, "reveal a robust peripheral signature of this amyloid chaperone protein that is responsive to key features of disease pathology.

"We suspect," said Dr. Lovestone "that we are moving towards a situation where very early, preclinical diagnosis or more accurate identification becomes possible with a combination of tests."

These might be blood tests, such as one being developed by Dr. Lovestone's team, and brain scans, including magnetic resonance imaging and positron emission tomography, as used in the current study.

The next steps, he said, are to first "design a better assay (the test itself) and then for us and other groups to replicate the finding. We are well on the way in the first of these objectives and expect to have the second completed within 3 years."

The researchers note that although their research implicates clusterin in AD pathology, there may well be other proteins in plasma related to the disease process, and indeed their previous studies and those of others suggest this is the case.

Intellectual property has been registered on the use of plasma proteins, including clusterin, for use as biomarkers for AD by King's College London and Proteome Sciences, with Dr. Lovestone and other coauthors named as inventors. Dr. Breitner has disclosed no relevant financial relationships.

Arch Gen Psychiatry. 2010;67:739-748.

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Authors and Disclosures

Journalist

Megan Brooks

Megan Brooks is a freelance writer for Medscape.

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