10-Lipid Profile May Identify Future Alzheimer's Patients

Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease

1. Anne M. Fagan, et. al.

1. ¹Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2. ²Knight Alzheimer’s Disease Research Center at Washington University School of Medicine, St. Louis, MO 63110, USA.
3. ³Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA.
4. ⁴Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
5. ⁵Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
6. ⁶Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
7. ⁷WA Center for Alzheimer’s Research and Care, Edith Cowan University, Perth, Western Australia 6009, Australia.
8. ⁸Mental Health Research Institute, University of Melbourne, Melbourne, Victoria 3052, Australia.
9. ⁹Department of Neurology, The Taub Institute and the Sergievsky Center, Columbia University, New York, NY 10032, USA.
10. ¹⁰Mary S. Easton Center for Alzheimer’s Disease Research, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
11. ¹¹Dementia Research Center, University College London, London WC1N 3BG, UK.
12. ¹²Departments of Neurology and Psychiatry, Warren Alpert Medical School of Brown University, Butler Hospital, Providence, RI 02906, USA.
13. ¹³Neuroscience Research Australia, Sydney, New South Wales 2031, Australia.
14. ¹⁴School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2031, Australia.
15. ¹⁵Department of Neurology, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
16. ¹⁶Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
17. ¹⁷http://www.dian-info.org/personnel.htm

1. ↵*Corresponding author. E-mail: fagana@neuro.wustl.edu

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-β_1–42 (Aβ_1–42) associated with the presence of Aβ plaques, and elevated concentrations of CSF tau, ptau₁₈₁ (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.

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