Blood Biomarker Predicts Dementia Pathogenesis

Quantitative immunoassays show that an increased level of a protein called clusterin is related to brain shrinkage, severity of memory problems and a risk of faster memory loss shown on the brain scans many years later. Clusterin, also known as apolipoprotein J, is a stress-induced cytoprotective chaperone protein, regulated by heat-shock factor protein 1 (HSF1), and functions similarly to a small heat-shock protein.

A team of scientists compared blood samples and brain scans from 300 participants with Alzheimer's disease (AD), mild cognitive impairment or normal cognition. They found that increased levels of clusterin, measured a decade earlier and correlated to the brain scans, were linked to amyloid plaques in the brain. Proteomic and genomic studies supported the conclusions.

The scientists discovered that APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques. Under the microscope, they observed clusterin to be surrounding the amyloid plaques in the mice's brain, indicating that clusterin might work to help protect the brain from amyloid protein. Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger ribonucleic acid (mRNA) in their blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.

The study conducted at King's College London (London, UK) was published in the July 2010 in the Archives of General Psychiatry. Madhav Thambisetty, M.D. Ph.D., the lead author said, "A primary goal in Alzheimer's research is to develop an inexpensive, easily administered test to accurately detect and track the progression of this devastating disease. Identifying clusterin as a blood biomarker that may be relevant to both the pathology and symptoms of the disease may bring us closer to this goal." These findings could lead to the development of a blood test to identify who would benefit from early treatment of AD and whether treatments were working to delay or prevent brain damage.

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