Major Finding: High clusterin levels were noted in 344 patients who had accelerated cognitive decline as well as in 237 subjects whose cognitive decline accelerated after their blood samples were obtained.
Data Source: Data from European centers participating in the AddNeuroMed study and the Baltimore Longitudinal Study of Aging.
Disclosures: The study was funded by the Alzheimer's Research Trust, and several other organizations. 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. Thambisetty and an associate named as coinventors.
Elevated plasma levels of a protein called clusterin appear to correlate with the degree of brain atrophy, the severity of symptoms, and the speed of the clinical progression of Alzheimer's disease, a report shows.
Moreover, clusterin levels appear to rise well before symptom onset or amyloid-beta deposition is noted in the seemingly healthy brains of older patients who go on to develop Alzheimer's disease.
Raised plasma clusterin concentrations were seen 10 years before amyloid-beta deposition, suggesting that clusterin plays an etiopathological role, and is not simply a reaction to other pathology in Alzheimer's disease (AD), according to Dr. Madhav Thambisetty, who was at the King's College Institute of Psychiatry, London, when he conducted the study with his associates. He is now with the Laboratory of Personality and Cognition in the Intramural Research Program at the National Institute of Aging, Bethesda, Md.
The findings do not endorse plasma clusterin level as a stand-alone biomarker for AD. “There may well be other proteins in plasma related to the disease process, and indeed our previous studies and those of others suggest this is the case,” they said.
Previous research has suggested that clusterin is one of several extracellular “chaperones” that regulate amyloid formulation and clearance. However, studies comparing clusterin levels in cerebrospinal fluid between AD patients and control subjects have produced inconclusive results.
In their study, Dr. Thambisetty and his colleagues used plasma proteomics and neuroimaging to identify proteins that might be associated with AD.
They identified 13 spots on gel electrophoresis that correlated with hippocampal atrophy in a sample of 44 patients who had mild cognitive impairment or mild to moderate AD, then performed the same analysis in a separate sample of 51 AD patients who clearly had either slow-progressing or fast-progressing AD. Only one protein – clusterin – was common to both groups in this discovery-phase study.
The researchers then confirmed the link between clusterin and AD in a validation cohort of 689 subjects from two European studies: 464 patients with AD, 115 with mild cognitive impairment, and 110 healthy controls. This time, they correlated clusterin levels with MR imaging that showed atrophy of the entorhinal cortex, a component of the medial temporal lobe that shows early pathological changes in AD.
Plasma clusterin also negatively correlated with cognitive scores on the Mini-Mental State Examination in a subset of 576 subjects, indicating a correlation between rising clusterin and declining cognition.
Further, higher clusterin levels were noted in patients with rapid progression of AD than in those with slower progression of AD. The association was observed in 344 patients who had shown accelerated cognitive decline before their blood samples were obtained and in 237 subjects whose cognitive decline accelerated after their blood samples were obtained.
Thus, the association was evident retrospectively and prospectively, relative to the time of blood sampling.
Data from a U.S. longitudinal study of aging were used to test the hypothesis that plasma clusterin level is a marker of future AD pathology in apparently healthy older adults. The researchers found that high clusterin levels predicted AD-associated changes on PET imaging as long as 10 years before those changes were evident.