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Levels of AD Biomarkers Rise and Fall After Dementia Becomes Evident

Fitzgerald, Susan

doi: 10.1097/01.NT.0000446543.34280.22
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Investigators reported that, over time, concentrations of CSF biomarkers of neuronal injury/death in autosomal-dominant Alzheimer's disease decreased, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression.

Three biomarkers associated with the death of neurons in Alzheimer's disease (AD) increase in the cerebrospinal fluid before symptoms develop, then decrease after dementia sets in, according to a new study of people with an inherited from of AD.

The study reinforces the hypothesis that the neuronal damage and cell death that are central to AD begin years and perhaps decades before clinical symptoms become apparent, and that the early phase may likely be the best time to intervene in the disease process.

Scientists have been studying AD-related biomarkers in the cerebrospinal fluid (CSF) and blood to measure progression of disease and, in the case of clinical trials, to look for signs of a positive response to the therapy being tested.

The new study showing that the trajectory of AD biomarkers is not a steady climb upward throughout the disease process could influence the design and interpretation of future trials, experts said.

“We think there is a robust stage of neuronal injury that appears early in the disease process, and then that phase of neuronal injury slows down in the symptomatic stage of the disease,” said Anne M. Fagan, PhD, research professor of neurology at Washington University School of Medicine in St. Louis and senior author of the study that was posted online March 5 in Science Translational Medicine. She said there is a growing body of AD research to support the theory that “there is a large preclinical stage of disease that likely spans 10, 20 years, maybe more,” Dr. Fagan told Neurology Today.

While there have been many studies that have focused on the trajectory of biomarkers indicative of amyloid and neuronal pathologies, this new study is different because it measured biomarker changes over time in individuals with rare autosomal-dominant Alzheimer's disease (ADAD). Such persons are certain to develop AD because of the genetic mutation and they may begin to experience signs of memory loss and other signs of cognitive decline as early as their 30s.

“This really is an ideal population to study to understand the pathology of Alzheimer's disease before people manifest any clinical signs of disease,” James E. Galvin, MD, a professor of neurology and psychiatry and Alzheimer's researcher at New York University (NYU) Langone School of Medicine, told Neurology Today. Dr. Galvin was not involved with the study.

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The Washington University investigators gathered data from participants enrolled in the DIAN study, the Dominantly Inherited Alzheimer Network, which is a international project involving researchers from multiple centers. Family members participating in the project are periodically evaluated using tests to measure AD biomarkers in CSF and plasma, as well as with imaging and neuropsychological tests. Since family members with the mutation tend to exhibit symptoms around the same age, researchers are able to predict where non-symptomatic individuals are on the timeline.

The research team focused on three biomarkers collected from CSF: tau and p-tau (phosphorylated tau) — proteins that form the neurofibrillary tangles found in the brains of people with AD — and VILIP-1 (visinin-like protein-1), a neuronal calcium sensor associated with cell death.

The researchers first looked at cross-sectional data on biomarkers collected from 146 mutation carriers and 96 non-carriers, which confirmed the idea that brain changes and damage is occurring long before there are symptoms. They reported that levels of amyloid-beta decrease while levels of tau, p-tau, and VILIP-1 increase in the CSF of “asymptomatic mutation carriers 10 to 20 years before their estimated age of symptom onset [EAO] and before the detection of cognitive deficits.”

The investigators collected serial amyloid measures. In general, the trajectories were as expected, with decreases in both before and after their expected age of onset. However, Dr. Fagan noted, the researchers also saw decreases in non-carriers, although values were overall much higher than in carriers, as expected. Amyloid-beta 42 levels in CSF of non-carriers varied much more than the accompanying changes in the injury markers.

The researchers also did another analysis that focused on 26 mutation carriers and 11 non-carrier siblings to measure changes in biomarker levels over time in each individual. As anticipated, levels went up in the pre-symptomatic stage, but acceleration did not continue when cognitive deficits set in.

“The concentration of CSF biomarkers of neuronal injury/death within individuals decrease after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression,” the researchers reported.

Why that switch occurs is not totally clear. “The decreases were not huge in amplitude but they were consistent and statistically significant,” Dr. Fagan said.

She said it was possible that the reverse trajectory of biomarkers was due to the fact that “that a certain large population of neurons die early, leaving a smaller population to die later.”

She said that a better understanding of AD biomarkers should help provide more precision in enrolling patients in clinical trials. If they are testing a potential AD therapy, researchers need to be sure that the study participant actually has the underlying pathology indicative of the disease. Also, knowing the anticipated pattern of biomarkers over time is crucial for knowing whether “drugs are doing what they are supposed to be doing,” Dr. Fagan said.

Dr. Fagan acknowledged that the team's study has limitations. The longitudinal analysis involved just a few dozen people and the CSF samples (two to three for each individual) were collected over just a two- to three-year span. A longer look is likely to be more revealing, she said.

Also, it is not possible to say with certainty whether the same pattern of biomarker changes would be observed in those with sporadic AD.

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Clifford Jack Jr., MD, a professor of radiology and the Alexander Family professor of Alzheimer's disease research at the Mayo Clinic in Rochester, MN, said the study's finding that there is an acceleration of changes in biomarker levels in the CSF followed by a deceleration is compatible with a hypothetical model of biomarker changes proposed by his research team in published papers.



“We hypothesized that the rate of change of all biomarkers, beginning with amyloid, didn't continue to accelerate indefinitely. All biomarkers would eventually plateau,” Dr. Jack, who was not involved with the current study, told Neurology Today. “The current paper, to the best of my knowledge, has the first data to indicate that tau approaches a plateau.”

Dr. Jack said the deceleration in levels of tau after clinically evident AD is reached is likely indicative of the fact that “there is a limited supply of vulnerable neurons” that can be affected by the disease pathology.

“I am of the school of thought that effective treatment is almost inevitably going to have to involve people early in the disease process,” he said, though he stressed that better therapies aimed at treating people with more advanced disease are also needed.

Dr. Galvin, of NYU, said that the latest study on biomarkers provides some encouraging news because it indicates a long window for intervening in AD.

“If you gave a drug in the early stage, then, in theory, you might be able to have a bigger impact on disease,” he said.

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•. Fagan AM, Xiong C, Jasielec MS, et al. for the Dominantly Inherited Alzheimer Network. Sci Transl Med 2014:6(226):226ra30.
    •. Benzinger TL, Blazey T, Jack CR Jr, et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease. Proc Natl Acad Sci USA 2013:110(47):E4502–4509.
      •. PubMed archive on Alzheimer's biomarkers:
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