TCD Researchers Develop a Second Groundbreaking New Test for the Prediction and Risk Assessment of Early Alzheimer’s Disease

Posted on: 15 April 2008

A major diagnostic breakthrough for Alzheimer’s disease has been developed by the Trinity College Dublin Chair of Psychiatry, Professor Harald Hampel, and his research team based at the Trinity College Institute of Neuroscience (TCIN) and the Adelaide & Meath Hospital incorporating the National Children’s Hospital (AMiNCH), Tallaght.  This is the second complimentary new discovery¹ in Alzheimer’s disease in recent months led by the TCD/AMiNCH research team and has been recently published in the world-leading peer-reviewed neurology journal, BRAIN², and top-level American Psychiatry journal Archives of General Psychiatry², and presented at the 2008 International Psychogeriatric Association (IPA) conference in Dublin last week.

In a collaboration with basic research partners from the United States³ the TCD researchers developed a new cerebrospinal fluid (CSF) based test for the detection of  early Alzheimer’s disease. The test allows for the CSF-based measurement of an enzyme called BACE1 that is known to be essential in the production of beta-amyloid (A?) which is progressively accumulated and deposited in the patient’s brains (‘amyloid plaques’) and represents a key mechanism in brain pathology in Alzheimer’s disease. The researchers’ findings pave the way for the assessment of BACE1 as an effective and accurate clinical diagnostic tool, which could significantly improve the early detection of the disease.

The prevalence of Alzheimer’s disease is projected to dramatically increase worldwide during the next decades. For Ireland, the projected increase will be approximately 43% within the next 20 years, entailing a large increase in costs for management, treatment and care of patients with the disease as well as their caregivers. Based on estimates in the year 2000, at least 30,000 patients with dementia are living in Ireland, with the annual costs of treatment of these patients accruing to about €474 million (National Council on Aging and Older People, 2000, National University of Ireland).

Commenting on the significance of this TCD-led new groundbreaking study, Professor Hampel stated: “These new findings reveal that subjects with mild cognitive impairment who are at increased risk of Alzheimer’s disease showed dramatically higher cerebrospinal fluid levels of the BACE1 biomarker than healthy elderly persons.  It means that the assessment of BACE1 could be of high clinical value for the early detection and risk assessment of Alzheimer’s disease in elderly persons”.

In the study recently published in the world leading Neurology journal BRAIN, data show that BACE1 is a primary candidate biomarker of increased risk of Alzheimer’s disease. The findings in a sample of 150 subjects, including candidates with Alzheimer’s disease, mild cognitive impairment, and older healthy subjects demonstrate that the major genetic risk factor of Alzheimer’s disease – a genotype called ApoE ?4 – is associated with increased concentration of the new BACE1 biomarker in cerebrospinal fluid. This genotype is the most important genetic risk factor known so far, accounting for up to 90% of the incidence of Alzheimer’s disease in persons less than 80 years old.

Commenting on the significance of the findings, Dr Michael Ewers, first author of the study and Senior Research Fellow in Professor Hampel’s team at TCIN and AMiNCH said: “The new biomarker is thought to measure the active production of beta-amyloid (A?) and is thus particularly apt to give insight into the actual state of progression of brain pathology in persons at risk of Alzheimer’s disease. This is especially valuable for the clinical prognosis of whether an elderly person with beginning mild cognitive impairment may be healthy or develop Alzheimer’s disease within a few years”.

Professor Hampel’s research group is clinically following up the subjects with mild cognitive impairment in order to examine whether BACE1 in cerebrospinal fluid predicts the development of Alzheimer’s disease within a clinically meaningful time interval of 2-3 years. Professor Hampel stated: “Preliminary results of the follow-up study provide a first promising hint that concentrations of the biomarker BACE 1 in combination with the ApoE genotype enable enhanced accuracy in the early pre-dementia detection and prognosis of an underlying ongoing Alzheimer’s disease manifestation in the patient’s brains. In a next substantial research step we are developing blood-based biomarkers and modern neuroimaging based methods to support early detection and prediction and to bring new effective treatments to Irish patients as soon as they become available. This promising research programme is  running at TCIN and AMiNCH, Tallaght.”

Volunteers over  the age of 55 years (healthy persons or persons with mild cognitive impairment or with established Alzheimer’s disease) interested in supporting this programme (focused on blood-based biomarkers and neuroimaging and participating in a current study of Professor Hampel at AMiNCH and TCIN may contact the research staff: Dr Yetunde Faluyi, 01 896 3697 /3706,

Notes to the Editor:

1. Other Discoveries: The latest developments with BACE1 are complementary to the previously published breakthrough with p-tau 231 by the TCD Chair of Psychiatry,  Professor  Hampel’s  research team which was recently published in the world-leading Neurology peer-reviewed clinical journal in December, 2007. The study shows that the biological marker in the brain called p-tau 231 is a significant predictor of cognitive decline and conversion in the transition from the clinically at risk syndrome, Mild Cognitive Impairment to Alzheimer’s disease. The group has thus developed two major complementary CSF-biomarker candidates covering the two major pathologies associated with AD, including the production of A? pathology as measured by the biomarker BACE1 and neurofibrillary tangles as measured by p-tau 231. Current studies are underway in order to test the predictive value for the combination of these two major CSF-biomarkers candidates, neuropsychological measures and genetic risk factors in order to optimize a highly disease-specific risk profile for the early detection of AD.

2. Brain 2008 Mar 11, Ewers M, Zhong Z, Bürger K, Wallin A, Blennow K, Teipel SJ, Shen Y, Hampel H.  Increased CSF-BACE 1 activity is associated with ApoE-?4 genotype in subjects with mild cognitive impairment and Alzheimer’s disease.

Archives of General Psychiatry 2007 Jun, 64(6): 718-26. Zhong Z, Ewers M, Teipel S, Bürger K, Wallin A, Blennow K, He P, McAllister C, Hampel H, Shen Y. Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment.

3. Dr Yong Shen, Haldeman Laboratory of Molecular and Cellular Neurobiology, Banner Health Research Institute, Sun City, Arizona, USA

4. About the Research Programme: These groundbreaking studies are part of a major international  large-scale research programme at the Trinity College Institute of Neuroscience (TCIN) and Adelaide & Meath Hospital incorporating the National Children’s Hospital (AMiNCH) that is internationally connected with the European multicentre Alzheimer’s Disease Neuroimaging Initiative (E-ADNI) of the European Alzheimer Disease Consortium (EADC) to develop innovative biomarkers and imaging technology for early detection and prediction of Alzheimer’s disease (AD). Professor Hampel is currently the Principal Investigator of the European ADNI Biomarker Programme and headed the recently completed large-scale six-years government funded German National Neuroimaging Reference Centre on Dementia. Professor Hampel’s Irish based research programme includes state-of-the-art methodology including neuropsychological assessment, blood-tests, genetic analysis, and structural as well as functional neuroimaging to develop biomarkers for the risk assessment and prediction of Alzheimer’s disease in elderly persons with beginning memory complaints. The successful realisation of this programme in Ireland is key to getting new effective treatments to patients as early as possible, even before irreversible damage has been inflicted to the brain. After rigorous evaluation and validation these biomarkers and imaging methods should be available within the next five years with the aim of placing Ireland at the international forefront in the battle against this devastating gigantic world-wide humanitarian, economic and health threat. The number of 26 Mio. Alzheimer’s patients today will dramatically quadruple within the next 40 years to over 105 Mio sufferers worldwide. Alzheimer’s has more new cases every year as conditions such as Stroke, Diabetes or breast cancer.

The current research study was specifically supported by grants from international and federal funding agencies including the Science Foundation Ireland (SFI), the National Institute on Aging (NIH, NIA), the Alzheimer Association (Chicago, USA), and the Federal Ministry of Education and Research (BMBF) in Germany.

5. About the Authors: Professor Hampel is the lead investigator on the European level for the development of biological markers for Alzheimer’s disease in the large-scale European Alzheimer’s Disease Neuroimaging Initiative (E-ADNI) as part of the European Alzheimer’s Disease Consortium (EADC) and headed the recently completed large-scale six-year government funded German National Neuroimaging Reference Centre on Dementia. Dr. Michael Ewers is Senior Research Fellow in Professor Hampel’s team at TCD and focuses on biostatistical analysis of biomarkers. Professor Hampel and his team’s research receives major funding by Science Foundation Ireland (SFI), the Irish Health Research Board (HRB), the National Institutes of Health (NIH) (USA), the German Federal Funding Agency (BMBF) and the Alzheimer Association (Chicago, USA).

The Irish Health Service Executive (HSE) and AMiNCH, Tallaght provided major support to Professor Hampel which made this world leading clinical research programme possible in Ireland.