Promise for early diagnosis of Alzheimer’s –
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.”
(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.
(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.
Prof. Dr. med. Harald Hampel, M.Sc.
Dementia Research Section and Memory Clinic, Alzheimer Memorial Center
Department of Psychiatry at LMU Munich