Biomarker Levels Differ Throughout Stages of Alzheimer's

A new study has reported unexpected patterns of three Alzheimer’s disease (AD) biomarkers of neuronal injury in research participants who are carriers of autosomal dominant AD mutations (ADAD).

“As the first longitudinal comparison of biomarker levels within individuals in the DIAN [Dominantly Inherited Alzheimer’s Network] cohort of members of families with known AD-causing mutations, we were able to compare the pattern of biomarker changes within mutation carriers (who will develop AD dementia with 100% certainty) as a function of where they were in the disease process (as defined by their estimated age of symptom onset which is predictable within families),” said lead researcher Anne M. Fagan, PhD, Department of Neurology, Washington University School of Medicine, and Knight Alzheimer’s Disease Research Center at Washington University School of Medicine, St. Louis, MO.
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Researchers observed within-person increases in biomarkers of neuronal injury during the preclinical period before the onset of symptoms, but decreases in levels of the same biomarkers later in the course of the disease when symptoms such as memory loss and mental decline are present.  

“These patterns suggest a robust phase of neuronal injury and death very early in the course of the disease, prior to symptoms, followed by a potential slowing of this process as symptoms progress,” she noted.

Cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data were collected at baseline from participants of the DIAN; all patients came from families with ADAD.

The authors found that levels of the biomarkers tau, p-tau, and visinin-like protein-1 (VILIP-1), which are markers of neurofibrillary tangles and neuronal injury/death, increased over time in those participants who were mutation carriers but had not yet developed symptoms and, when compared longitudinally, decreased over time in most participants with dementia.

Because it is commonly thought that biomarkers of neuronal injury/death continue to increase over time as an individual’s disease progresses, “We were initially surprised tosee that these markers were actually decreasing over time once even the earliest symptoms became apparent,” said Fagan.

“This observation does not mean that neuronal degeneration does not continue through the symptomatic phase—we know that brain atrophy continues—but rather it suggests that neuronal degeneration starts prior to symptoms and continues as the disease progresses through its symptomatic phase, but its rate may be slower relative to earlier stages,” she continued.

Another possibility is that decreases in injury biomarker levels may also reflect fewer neurons remaining that can contribute to the biomarker levels in the CSF. “These scenarios are not mutually exclusive,” said Fagan.

Fagan stated that their data “support a model in which biomarker trajectories differ as a function of where an individual falls in the neuropathological cascade, and thus emphasizes the importance of within-person assessment of changes in biomarkers over time as opposed to a measure at a single time point when evaluating disease progression.”

Specifically, the findings suggest a potential modification to the proposed model to incorporate an eventual deceleration of the rate of neuronal injury and death with a patient’s symptomatic disease progression, she explained.

“If corroborated in additional cohorts, this pattern of marker change will likely have an impact on the definition of a positive neurodegenerative biomarker outcome in clinical trials, especially during the symptomatic phase.”

Some study limitations, as noted by Fagan, include the fact that because the findings were observed in carriers of rare disease-causing mutations, “the generalizability to the more common ‘sporadic’ form remains to be determined.” The small number of participants in the longitudinal cohort (26 mutation carriers) and the small number of repeat CSF samples per person (2-3) are other limitations.

“Future analyses in the expanding DIAN cohort, with greater numbers of longitudinal samples collected per person, will allow us to evaluate the validity and robustness of these biomarker findings,” she said.

This study is available in Science Translational Medicine.

-Meredith Edwards White

Reference

Fagan AM, Xiong C, Jasielec MS, et al; Dominantly Inherited Alzheimer Network. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Sci Transl Med. 2014 Mar 5;6(226):226ra30. doi: 10.1126/scitranslmed.3007901.