With the current study, Dr. Zetterberg stated, “The basic questions we are trying to address are: ‘When do these biomarkers turn positive?’ and ‘When can we detect Alzheimer’s disease by measuring these proteins?’”
To answer these questions, Dr. Zetterberg and his colleagues performed lumbar puncture on 137 people with MCI and clinically followed them for more than nine years. “During the whole study, 72 of the 137 patients with MCI converted to Alzheimer’s disease,” Dr. Zetterberg told Neurology Reviews. “Fifty-seven of 137 converted to Alzheimer’s disease during the first follow-up (mean, five years); an additional 15 converted to Alzheimer’s disease during the second follow-up (mean, nine years).” Sixteen percent of the study population progressed to other forms of dementia. Compared with nonconverters, the investigators reported, those who converted to Alzheimer’s disease had a positive biomarker signature, consisting of elevated total-tau and phospho-tau levels and decreased amyloid-beta 42 levels.
When the investigators examined early conversion (from MCI to Alzheimer’s disease within five years from baseline) and late conversion (between five and 10 years after baseline), they found that amyloid-beta 42 levels at baseline were equally reduced in all patients; total-tau and phospho-tau levels, however, were significantly higher in early converters compared with late converters. “CSF amyloid-beta 42 seems to be an earlier biomarker than CSF tau proteins,” Dr. Zetterberg said. “High CSF tau protein levels indicate an intense neurodegenerative process and predict rapid progression to dementia.”
When using a ratio of baseline amyloid-beta 42 and phospho-tau, the researchers were able to predict the development of Alzheimer’s disease within 9.2 years, with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%. “In this study, we showed that around 90% of MCI patients with pathologic CSF biomarkers at baseline will develop Alzheimer’s disease within nine to 10 years,” Dr. Zetterberg concluded. “Our results suggest that the CSF biomarker profile is highly predictive.
“The current implication is to select early Alzheimer’s disease patients for clinical trials and to monitor biochemical effects of new treatments on Alzheimer’s disease pathology,” Dr. Zetterberg pointed out. “If any of these trials is positive, there will be an immediate clinical need for the biomarkers to determine which of the early patients really suffer from Alzheimer’s disease and are in need of treatment with the new drug.”
A Time Line for Alzheimer’s Disease Testing?
“This work represents a good first step toward a population-based screening test for Alzheimer’s disease, but there is a lot of further work to be completed to achieve this goal,” said Dr. Burnham, citing the search for other biomarkers as a primary focus of the AIBL program. “Once we are satisfied with the biomarkers, we will need to further validate them, including looking at other disease cohorts for specificity and in-population screening. It will also be necessary to format tests onto a platform suitable for widespread screening.”
She also outlined future goals of the current study: “As we progress with monitoring our cohort over time, we will be able to see how the model tracks with progression to the disease…. We hope that as we move toward the 54-month collection point, we will have better indicators of the efficacy of such a test.
“PET imaging is generally used as a research tool because of the amount of cost and the lack of accessibility to it. There are other CSF markers that have been shown to correlate with plaque as well, but we looked at a blood test for economic and accessibility reasons,” Dr. Burnham explained.
Addressing the concerns regarding safety and invasiveness of the lumbar puncture procedure, Dr. Zetterberg said, “The spinal tap might scare some people, but it is a safe procedure that might have one possible complication, and that is postlumbar puncture headache, which occurs in about 2% to 3% of patients.” The procedure also has advantages when compared with blood analysis, he noted. “The advantage with analyzing CSF is that you get across the blood-brain barrier,” Dr. Zetterberg said. “The blood is much more difficult to find reliable proteins in—there are great possibilities, but it’s more difficult.”
Regarding the future of a CSF test for the disease, Dr. Zetterberg added, “Total-tau, phospho-tau, and amyloid-beta 42 are the best-studied biomarkers. They show the greatest differences with regards to Alzheimer’s disease, and they also have the most direct link to the neuropathology of Alzheimer’s disease. But most likely in the future, we will find additional markers.”
Suggested Reading
Cui Y, Liu B, Luo S, et al. Identification of conversion from mild cognitive impairment to Alzheimer’s disease using multivariate predictors. PLoS One. 2011 July 21; [Epub ahead of print].
Johansson P, Mattsson N, Hansson O, et al. Cerebrospinal fluid biomarkers for Alzheimer’s disease: diagnostic performance in a homogeneous mono-center population. J Alzheimers Dis. 2011;24(3):537-546.
Sona A, Zhang P, Ames D, et al. Predictors of rapid cognitive decline in Alzheimer’s disease: results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing. Int Psychogeriatr. 2011 July 13; [Epub ahead of print].
Watt AD, Perez KA, Faux NG, et al. Increasing the predictive accuracy of amyloid-b blood-borne biomarkers in Alzheimer’s disease. J Alzheimers Dis. 2011;24(1):47-59.