Global research initiatives to standardize Alzheimer's biomarkers

As the Alzheimer's field moves closer to new and earlier tests for the disease, innovative global research initiatives are taking the first important steps to standardize Alzheimer's biomarkers, as evidenced by two presentations made today at the Alzheimer's Association(R) International Conference 2011 (AAIC 2011) in Paris.

One study compared, for the first time, results of brain amyloid imaging and the impact of genetics and ethnicity on those results across countries on three different continents as part of a worldwide Alzheimer's disease imaging study. The other takes a significant step forward in creating a standard international method for measuring the size of a key memory center in the brain (the hippocampus) - which often is one of the first brain areas affected by Alzheimer's.

"We need to identify people in the earliest stages of Alzheimer's, even those without outward evidence of memory and thinking symptoms, for treatment and prevention trials," said Maria Carrillo, Ph.D., senior director of Medical and Scientific Relations at the Alzheimer's Association. "It is very important that the tests are accurate and effective, and that they are delivered and measured in the same way across the world so that measures are comparable."

"For example, if you get your blood tested for cholesterol levels in Budapest, Bangalore or Boston, the methods are the same and the results are comparable. That is not yet the case for Alzheimer's disease, especially for assays that detect Alzheimer's proteins in blood or cerebrospinal fluid," Carrillo said. "To ensure comparable results, the methods used for gathering and evaluating samples must be consistent. As an illustration, spinal fluid gathered or stored in a plastic container may give different results than a sample gathered or stored in a glass container."

The Alzheimer's Association is taking the lead in a number of global efforts to standardize Alzheimer's biomarkers, in particular with the creation and management of the World Wide Alzheimer's Disease Neuroimaging Initiative (WW-ADNI) and the Alzheimer's Association Cerebrospinal Fluid (CSF) Quality Control Program.

WW-ADNI is the umbrella organization for neuroimaging initiatives being carried out through the North American ADNI, European ADNI (E-ADNI), Japanese ADNI, Australian ADNI (AIBL), and Taiwan ADNI. The overall goals of WW-ADNI are to better understand the physical changes that occur in healthy individuals compared with individuals with mild cognitive impairment (MCI) and Alzheimer's, and to develop improved methods for identifying the appropriate patient populations for clinical trials. WW-ADNI also aims to standardize the methods used for conducting imaging scans and gathering and testing fluid samples so that data from all sites can be readily combined and easily understood by researchers. Data from WW-ADNI are expected to play a key role in identifying effective treatments for Alzheimer's, as well as methods that may prevent or slow the progression of the disease.

Launched in fall 2009, the Alzheimer's Association Cerebrospinal Fluid (CSF) Quality Control Program brings together laboratories across the globe with the aim of standardizing the measurement of potential Alzheimer biomarkers. More than 60 labs in North and South America, Asia, Australia and Europe are participating in the program. CSF biomarkers may be useful not only in aiding early detection of Alzheimer's and improving diagnostic accuracy, but also in identifying and monitoring the effects of drugs in clinical trials, understanding the molecular changes that lead to Alzheimer's, and helping to ensure that individuals recruited into Alzheimer clinical trials are on a path toward developing the disease. The program is fully supported by a gift from the Dana and Dave Dornsife family.

"To enable people to live their lives without the dementia caused by Alzheimer's, early detection of the disease and effective treatment are essential," Carrillo said. "These two research efforts, and others like them, will be instrumental in getting us there."

Alzheimer's Disease Neuroimaging Data from Three Countries

It has not been established whether the association between a well- established Alzheimer's risk gene - apolipoprotein E (APOE) e4 - age, and amyloid deposition is consistent among ethnic groups.

Kenji Ishii, M.D., of Tokyo Metropolitan Institute of Gerontology, and colleagues, used data from three multi-center studies of Alzheimer's that are using a harmonized protocol - the Alzheimer's Disease Neuroimaging Initiative (US-ADNI), Australian Imaging Biomarker and Lifestyle Flagship Study of Aging (AIBL), and Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) - to evaluate the influence of APOE e4 and age on the accumulation of amyloid in the brain as measured by PET scan with 11C-Pittsburgh compound B (PiB). This is the first report of an international ADNI data analysis including these three different national populations, all three of which include people with Alzheimer's, MCI, and cognitively normal individuals.

The researchers found that:

The effect of age and APOE-e4 on amyloid deposition in the Japanese population is similar to Caucasians, despite a lower e4 allele frequency in the Japanese population.

In the cognitively normal people in the study, having a single copy of the APOE-e4 gene is roughly equivalent to 12 additional years of age for PiB positivity.

Perhaps most importantly, for the Alzheimer's research field, the results suggest that the three multi-national ADNI data sets are feasible for combined analysis.

"This is one of the first demonstrations of the great value of open data sharing in the worldwide ADNI initiative," Ishii said. "Combined analysis enlarges and diversifies the study population and the data set. It increases the power of the results, decreases ethnicity effects and makes the findings more broadly applicable. This is very important as we identify and verify biomarker tests for Alzheimer's disease."

Towards a Harmonized Protocol for Measuring the Hippocampus

The earliest Alzheimer's related brain changes are usually seen in the hippocampus, the "control center" of memory-related activity in the brain. In previous studies, MRI measurement of shrinkage of the hippocampus over time has shown value for diagnosis of Alzheimer's and tracking the progression of the disease. But harmonization (greater standardization) in assessing volume change is needed as researchers work to move hippocampal measurement from research centers into wider clinical use.

A variety of published protocols now exist for assessing hippocampal volume. These protocols differ because they rely on various techniques of "segmentation" - that is, assigning the electronic image voxels (volumetric pixels) to specific structures, such as the hippocampus, within the brain.

As a first phase of the standardization process, Giovanni Frisoni, M.D., of San Giovanni di Dio Fatebenefratelli, Brescia, Italy, and colleagues surveyed the various available segmentation protocols to identify underlying reasons why they result in different volume estimates. This work was funded by the Alzheimer's Association.

"The next step will be to create, test and verify a single protocol for MRI-based evaluation of Alzheimer's disease-related hippocampal shrinkage," Frisoni said. "This initial quantification will help our international panel of experts define which key components should be included in an international harmonized protocol."