Ten genes are now linked to Alzheimer’s disease through genomewide association studies (see ARF related news story). Genetic variations in and around these genes either protect against or predispose to the disease, though for most of them it is not clear why. In this week’s Journal of the American Medical Association, a hint is beginning to emerge for one of them, clusterin, also known as apolipoprotein J.

Researchers led by Monique Breteler at Erasmus University Medical Center, Rotterdam, The Netherlands, report that a person’s plasma levels of the protein correlate with how severe disease is in them, though not with incidence of emerging disease. The finding to the authors implies that the protein might be neuroprotective. “We don’t know how, but it may be part of a generic mechanism that gets triggered when something goes wrong,” Breteler told ARF.

More than ten years ago, post-mortem analysis carried out by researchers at Kaj Blennow’s lab in Goteborg University, Sweden, indicated that clusterin is elevated in the brains of people with AD (see Lidström et al., 1998). Those researchers failed to find any corresponding change in cerebrospinal fluid levels (Lidström et al., 2001). Nevertheless, a link between AD and plasma clusterin emerged. A research collaboration led by Simon Lovestone at King’s College, later London, U.K., reported last year that patients with more severe dementia had higher levels of the protein in their blood (see ARF related news story). Breteler now found the same thing in a bigger sample of patients.

Also, looking longitudinally at data from patients and normal controls, they found that plasma clusterin did not predict who would get AD over the ensuing three years. First author Elisabeth Schrijvers and colleagues tested plasma samples from 926 of the original Rotterdam Study, a population-based survey of 5,990 older adults begun in 1997. People with the highest levels of plasma clusterin (top quartile) were three times more likely to have AD.

“This is a great study and an exciting result,” said Lovestone. “The word on the street is that blood-based biomarkers for Alzheimer’s disease don’t replicate. I think Breteler has put paid to that,” he told ARF. One difference between the two studies is that Lovestone’s data hinted that clusterin might be an early marker of AD, since he found that normal controls with high brain amyloid had high plasma clusterin. One of the key questions, said Lovestone, is “At what point does plasma clusterin go up?”

Schrijvers and colleagues found no hint that plasma clusterin is an early marker. In fact, Breteler told ARF that it may not be useful as a biomarker. Doug Galasko, University of California, San Diego, agreed. “I’m not sure it is going to change the way we appraise risk or progression, but as part of a panel of markers it may have some utility,” he suggested. Galasko also cautioned that is it not clear that what is being detected in the plasma is coming from the brain. There could be systemic effects associated with poor general health in severe AD cases, he suggested.

Even if plasma clusterin is not practical as a biomarker, it may still be important. “The fact that we only see levels increase post hoc does not preclude that clusterin is causally involved in AD,” said Breteler. How so remains to be seen. The protein has many potential roles, being involved in innate immune reactions, lipid metabolism, and amyloid-β (Aβ) clearance. Knocking out clusterin protects transgenic mice against Aβ toxicity (see ARF related news story). However, knocking out both clusterin and ApoE seems to make matters worse (see ARF related news story). “At this stage I don’t think it is helpful to speculate on what clusterin might be doing,” said Breteler. “This is why it is so important that we get into translational research.”—Tom Fagan

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Comments on News and Primary Papers

  1. I have been interested in clusterin for some time, as it is somewhat similar to ApoE in several ways. Clusterin is produced at high levels in the brain by astrocytes (like ApoE), It occurs in HDL-like particles in the brain (like ApoE), and it strongly increases amyloid formation and neurite toxicity in APP transgenic mice (DeMattos et al., 2002).

    In this paper by the Breteler group, clusterin was found to be increased by about 10 percent in the plasma of AD patients compared to controls in this population-based study. There were not many AD cases studied for clusterin levels (only 60), though there were large numbers of non-AD cases. Plasma clusterin was found to be increased with increasing AD severity. These are interesting findings, though the changes are somewhat small.

    I am also aware of unpublished studies comparing plasma clusterin in AD and control plasma which so far have not found differences between the groups. However, these studies are not in epidemiologically ascertained sample sets.

    So, while the paper from the Breteler group is interesting, it would be useful to see if this is replicable in other sample sets.

    View all comments by David Holtzman
  2. Using Rules-Based Medicine techniques and samples from a large population-based cohort, the authors show that clusterin levels in plasma are slightly elevated in Alzheimer's disease and also in other dementia forms as compared to non-demented individuals. They also demonstrate that this change is downstream of the dementia phenotype and not related to its pathogenesis. This result is similar to what has been seen, for example, for α1-antichymotrypsin and some other inflammatory markers, and provides information of limited diagnostic value.

    View all comments by Henrik Zetterberg

References

News Citations

  1. Large Genetic Analysis Pays Off With New AD Risk Genes
  2. Research Brief: Clusterin Grabs Spotlight Among Elite Few LOAD Genes
  3. Stockholm: Clusterin (or Beware the Evil Chaperone!)
  4. Lipoproteins and Amyloid-β—A Fat Connection

Paper Citations

  1. . Clusterin (apolipoprotein J) protein levels are increased in hippocampus and in frontal cortex in Alzheimer's disease. Exp Neurol. 1998 Dec;154(2):511-21. PubMed.
  2. . Normal levels of clusterin in cerebrospinal fluid in Alzheimer's disease, and no change after acute ischemic stroke. J Alzheimers Dis. 2001 Oct;3(5):435-442. PubMed.

Further Reading

Papers

  1. . Clusterin (apolipoprotein J) protein levels are increased in hippocampus and in frontal cortex in Alzheimer's disease. Exp Neurol. 1998 Dec;154(2):511-21. PubMed.
  2. . Normal levels of clusterin in cerebrospinal fluid in Alzheimer's disease, and no change after acute ischemic stroke. J Alzheimers Dis. 2001 Oct;3(5):435-442. PubMed.

Primary Papers

  1. . Plasma clusterin and the risk of Alzheimer disease. JAMA. 2011 Apr 6;305(13):1322-6. PubMed.