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Promise for early diagnosis of Alzheimer’s –

Brain Enzyme may allow risk assessment and detection

Munich, 07/30/2008

With the continued aging of the population and the growing epidemic of Alzheimer’s, early detection of the disease is crucial for risk assessment, testing new therapies, and eventual early intervention with better drugs, once they are developed. As reported yesterday at the Alzheimer’s Association’s 2008 International Conference on Alzheimer’s Disease (ICAD 2008) in Chicago, the work of LMU-researchers under the lead of Professor Harald Hampel, based on recent publications, is one of a few promising approaches to reach the goal of early detection with the help of so-called biomarkers. A biomarker is a substance or characteristic that can be objectively measured and evaluated as an indicator of normal body processes, disease processes, or the body’s response(s) to a therapeutic intervention. Elevated activity of the enzyme β-secretase (BACE1) has been found in the brains of patients with Alzheimer’s compared to healthy individuals. BACE1 is crucial for the production of toxic beta amyloid plaques in the brains of people with Alzheimer's. Hampel’s team has shown that patients with mild cognitive impairment (MCI) – a condition that can develop into Alzheimer’s – show highly increased levels of BACE1 in their cerebrospinal fluid and that the enzyme is one of the strongest predictors of conversion from MCI to Alzheimer’s. “We are currently working on a blood-based diagnostic test for BACE1,” says Hampel. “Overall, the enzyme could prove as an effective and accurate clinical diagnostic tool to improve risk assessment and early detection of the disease.”

It is widely believed that Alzheimer’s disease brain changes, including amyloid plaques and neurofibrillary tangles, begin many years before symptoms are evident or there is significant death of brain cells. It is critical to identify affected individuals while they are still cognitively normal so that future disease modifying therapies can preserve normal function. The testing and eventual use of such therapies requires identification of affected and “at risk” individuals in order to steer them to clinical trials, and to direct and monitor therapy.

Professor Harald Hampel, of Trinity College Dublin, Ireland and Ludwig-Maximilians-Universität (LMU) München, Germany, Professor Yong Shen, of Sun Health Research Institute, USA, and colleagues investigated whether BACE1 assessed in cerebrospinal fluid (CSF) may be a feasible biomarker candidate for predicting Alzheimer’s in people with mild cognitive impairment (MCI). MCI is a transition stage between the cognitive changes of normal aging and the more serious problems caused by Alzheimer's.

The research had two parts. In the first part, the scientists measured BACE1 levels in CSF in 80 people with Alzheimer’s, 59 people with MCI, and 69 healthy elderly controls (HC) at two independent, international research centers. MCI subjects showed highly increased levels of BACE1 activity when compared to HC and people with Alzheimer’s. BACE1 activity was significantly correlated with Aβ level. A subsequent validation study replicated these initial findings in a new and independent set of 41 people with Alzheimer’s, 46 with amnestic MCI and elderly HC.

In the second part, 47 MCI subjects were clinically followed up over two years to assess the predictive value of BACE1 in combination with other biomarker candidates for predicting the conversion from MCI to Alzheimer’s. The additional candidates were abnormal brain proteins total tau and phosphorylated tau measured in CSF, and baseline performance on a large neuropsychological testing battery. Fifteen (15) MCI subjects converted to Alzheimer’s after a mean follow-up interval of 2.3 years. Analysis showed that BACE1 protein levels and ApoE genotype (a genetic risk factor for Alzheimer’s) were the strongest predictors of conversion to Alzheimer’s, after controlling for age and gender. The classification accuracy was 78%, the sensitivity was 80%, and the specificity was 77% for the combined model.

“These important findings pave the way for further rigorous assessment of BACE1 as an effective and accurate clinical diagnostic tool, which could significantly improve risk assessment and early detection of Alzheimer’s,” Hampel said. “We believe that BACE1 will be an excellent outcome biomarker to look at in ongoing clinical trials of anti-amyloid, disease modifying therapies. Furthermore, we are working on a blood-based diagnostic test for BACE1 as well.”

 

Publications:
(1) “Increased CSF-BACE 1 activity is associated with ApoE-ε4 genotype in subjects with mild cognitive impairment and Alzheimer's disease“
Ewers M, Zhong Z, Bürger K, Wallin A, Blennow K, Teipel SJ, Shen Y, Hampel H.
http://brain.oxfordjournals.org/cgi/content/full/awn034v1
(2) “Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment.”
Zhong Z, Ewers M, Teipel S, Burger K, Wallin A, Blennow K, He P, McAllister C, Hampel H, Shen Y.
Arch Gen Psychiatry 2007;64:718-726.
(3) “Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI.”
Ewers M, Buerger K, Teipel SJ, Scheltens P, Schröder J, Zinkowski RP, Bouwman FH, Schönknecht P, Schoonenboom NS, Andreasen N, Wallin A, DeBernardis JF, Kerkman DJ, Heindl B, Blennow K, Hampel H.
Neurology, 2007; 69(24):2205-12.

Contact:
Prof. Dr. med. Harald Hampel, M.Sc.
Dementia Research Section and Memory Clinic, Alzheimer Memorial Center
Department of Psychiatry at LMU Munich
Tel:  +49-89-5160-5814
Fax: +49-89-5160-5814
Email: Harald.Hampel@med.uni-muenchen.de

 

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