Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease

Anne M. Fagan, Chengjie Xiong, Mateusz S. Jasielec, Randall J. Bateman, Alison M. Goate, Tammie L S Benzinger, Bernardino Ghetti, Ralph N. Martins, Colin L. Masters, Richard Mayeux, John M. Ringman, Martin N. Rossor, Stephen Salloway, Peter R. Schofield, Reisa A. Sperling, Daniel Marcus, Nigel J. Cairns, Virginia D. Buckles, Jack H. Ladenson, John C. MorrisDavid M. Holtzman

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

Clinicopathological evidence suggests that the pathology of Alzheimer's disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic ("preclinical") stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-β1-42 (Aβ1-42) associated with the presence of Aβ plaques, and elevated concentrations of CSF tau, ptau 181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.

Original languageEnglish
Article number226ra30
JournalScience Translational Medicine
Volume6
Issue number226
DOIs
StatePublished - Mar 5 2014

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Cerebrospinal Fluid
Alzheimer Disease
Biomarkers
Amyloid
Neurocalcin
Neurobehavioral Manifestations
Mutation
Neurofibrillary Tangles
Wounds and Injuries
Age of Onset
Disease Progression
Clinical Trials
Pathology
Brain

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fagan, A. M., Xiong, C., Jasielec, M. S., Bateman, R. J., Goate, A. M., Benzinger, T. L. S., ... Holtzman, D. M. (2014). Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Science Translational Medicine, 6(226), [226ra30]. https://doi.org/10.1126/scitranslmed.3007901

Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. / Fagan, Anne M.; Xiong, Chengjie; Jasielec, Mateusz S.; Bateman, Randall J.; Goate, Alison M.; Benzinger, Tammie L S; Ghetti, Bernardino; Martins, Ralph N.; Masters, Colin L.; Mayeux, Richard; Ringman, John M.; Rossor, Martin N.; Salloway, Stephen; Schofield, Peter R.; Sperling, Reisa A.; Marcus, Daniel; Cairns, Nigel J.; Buckles, Virginia D.; Ladenson, Jack H.; Morris, John C.; Holtzman, David M.

In: Science Translational Medicine, Vol. 6, No. 226, 226ra30, 05.03.2014.

Research output: Contribution to journalArticle

Fagan, AM, Xiong, C, Jasielec, MS, Bateman, RJ, Goate, AM, Benzinger, TLS, Ghetti, B, Martins, RN, Masters, CL, Mayeux, R, Ringman, JM, Rossor, MN, Salloway, S, Schofield, PR, Sperling, RA, Marcus, D, Cairns, NJ, Buckles, VD, Ladenson, JH, Morris, JC & Holtzman, DM 2014, 'Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease', Science Translational Medicine, vol. 6, no. 226, 226ra30. https://doi.org/10.1126/scitranslmed.3007901
Fagan AM, Xiong C, Jasielec MS, Bateman RJ, Goate AM, Benzinger TLS et al. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Science Translational Medicine. 2014 Mar 5;6(226). 226ra30. https://doi.org/10.1126/scitranslmed.3007901
Fagan, Anne M. ; Xiong, Chengjie ; Jasielec, Mateusz S. ; Bateman, Randall J. ; Goate, Alison M. ; Benzinger, Tammie L S ; Ghetti, Bernardino ; Martins, Ralph N. ; Masters, Colin L. ; Mayeux, Richard ; Ringman, John M. ; Rossor, Martin N. ; Salloway, Stephen ; Schofield, Peter R. ; Sperling, Reisa A. ; Marcus, Daniel ; Cairns, Nigel J. ; Buckles, Virginia D. ; Ladenson, Jack H. ; Morris, John C. ; Holtzman, David M. / Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. In: Science Translational Medicine. 2014 ; Vol. 6, No. 226.
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