Investigators reported that increased levels of clusterin do not precede development of AD and therefore are not a potential early marker of subclinical disease.
DR. MONIQUE BRETELER: “Our data underscore the need for further research to understand the role of clusterin in AD. This may ultimately lead to better treatment or prevention options.”
Elevated levels of clusterin in the blood are associated with cases of Alzheimer disease (AD), but measuring the protein is not useful for predicting whether someone will develop the disease, according to a new population-based study from the Netherlands. The study also found that higher levels of clusterin correspond with more severe disease.
“Increased levels of clusterin do not precede development of AD and therefore are not a potential early marker of subclinical disease,” concluded the research team, based at Erasmus MC University Medical Center in Rotterdam. The researchers reported their findings in the April 6 edition of The Journal of the American Medical Association (JAMA).
Alzheimer researchers are interested in clusterin because several genetics studies have linked the CLU gene, which encodes for the protein, to AD.
“The protein clusterin, also known as apolipoprotein J, has been suggested to be involved in the pathogenesis of AD,” according to background information in the published report. “Clusterin has been found in the frontal cortex and hippocampus of post-mortem AD brains and is increased in the CSF of patients with AD. Plasma clusterin was reported to be associated with brain atrophy, baseline disease severity, and rapid clinical progression in AD, suggesting its possible use as a biomarker for AD.”
To test that possibility, researchers drew from data collected as part of the Rotterdam Study, a large prospective population-based cohort study that includes residents aged 55 or older of Ommoord, a district of Rotterdam. Baseline exams of participants were done between 1990 and 1993 and follow-up exams were conducted in 1993-94, 1997-199 and 2002-2004.
Researchers used a three-part protocol at each of the study points to determine if participants had dementia. First, study volunteers were given two tests of cognition — the Mini-Mental State Examination (MMSE) and Geriatric Mental State Schedule organic level. If either test indicated a problem, participants were then administered the Cambridge Examination for Mental Disorders of the Elderly. A neuropsychologist examined participants thought to have dementia, and diagnoses of dementia and AD were made using internationally accepted criteria.
The analysis published in the JAMA article was carried out using measurements of plasma clusterin in 60 participants in the Rotterdam Study who had AD at baseline, a random subcohort of 926 participants without AD and another 156 participants who were diagnosed with AD during the course of the follow-up years.
“The likelihood of prevalent AD increased with increasing plasma levels of clusterin,” the researchers reported. Specifically, the chances of a participant having prevalent AD increased by 63 percent for each standard deviation in clusterin levels, they noted. The association held after statistical adjustments were made for sex, education, apoliprotein E, diabetes, smoking, coronary heart disease and hypertension. Higher clusterin levels were associated with more severe disease. There was also a connection between elevated levels of clusterin and all-cause dementia and vascular dementia.
But clusterin was not a good indicator of risk for developing AD.
“There was no statistically significant association of plasma clusterin levels with incident AD during total follow-up or with incident AD within or after 3 years of baseline,” the researchers reported.
“Our findings strongly suggest that clusterin is not useful as an early diagnostic biomarker for AD,” Monique Breteler, MD, professor of neuroepidemiology at Erasmus MC University Medical Center, Rotterdam, and a member of the research team — told Neurology Today in an e-mail response to questions. But that doesn't mean clusterin should be ignored. “Our data underscore the need for further research to understand the role of clusterin in AD,” Dr. Breteler said. “This may ultimately lead to better treatment or prevention options.”
Her team wrote that “our data do not support the suggestion that clusterin is increased, possibly as an etiopathological event, before the development of AD, but fits the hypothesis that the increased expression of clusterin in AD reflects a neuroprotective response.”
Some research has suggested that clusterin plays a protective role in the brain, perhaps by “inhibition of amyloid formation through binding amyloid-beta or enhancing its clearance over the blood-brain barrier,” the researchers reported. “The neurodegenerative changes that occur in AD may trigger an increased expression of clusterin.”
They noted that the finding that elevated clusterin was also associated with all-cause dementia and vascular dementia suggests that the protein plays a “reactive rather than causative role.”
“This suggests that clusterin is involved in a mechanism that is not solely confined to pure AD but in a wide range of neurodegenerative diseases,” Dr. Breteler told Neurology Today.“A consequence is that measurement of clusterin levels does not seem useful for differential diagnostic purposes.”
DR. DAVID S. KNOPMAN: “Clusterin has many putative mechanisms by which it could infl uence AD pathology. It might provide a key insight into the genetic cascade involved in Alzheimer disease.”
David S. Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, MN, told Neurology Today that while the study made an interesting observation that clusterin is elevated in Alzheimer patients, the fact that the protein was not predictive of coming problems “weakens the story.”
He said more research on clusterin is warranted, but for now it's not something doctors would order to diagnose or predict the development of disease. One avenue for exploration is to figure out more precisely how clusterin fits into the disease process, he said. “Clusterin has many putative mechanisms by which it could influence AD pathology. It might provide a key insight into the genetic cascade involved in Alzheimer disease.”
David Holtzman, MD, professor and chairman of neurology at Washington University in St. Louis, said he read the paper out of the Netherlands with interest because he is also doing research on the role of clusterin.
“It turns out we've studied the same protein in the blood and did not find any change between cognitively normal controls and AD. However, our research subjects were not from an epidemiologically-based sample as was assessed in this study,” he told Neurology Today.
Researchers would like to identify a biomarker or set of biomarkers that could be part of a simple blood test to flag early cases of AD or even people at high risk for developing the disease.
“An accurate blood biomarker would be a game changer,” Dr. Holtzman said.