Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease
Open accessAbstract
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, 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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The first biomarkers to become abnormal in carriers of deterministic AD mutations are those of Aβ.
“The first biomarkers to become abnormal in carriers of deterministic AD mutations are those of Aβ [9–11,14].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [14]
The Discussion proposes a sequence in which Aβ1-42 changes very early in mutation carriers, followed by increases in tau and other injury markers. But it presents this as a suggested model, not an established ordering of the first abnormal biomarkers. The Results also report elevated CSF ptau181 about 20 years before estimated symptom onset, while the Discussion says the apparent very-early CSF Aβ1-42 difference was not statistically established. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe imperfect correlation between tau PET and CSF P-tau may be in part because P-tau plateaus later in the disease while tau PET signal continues to increase.
“This may be in part because P-tau seems to plateau later in the disease [14] while the tau PET signal continues to increase [124].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [14]
The Results and Discussion report that CSF ptau181 rises early in autosomal-dominant Alzheimer’s disease but decreases at later, typically symptomatic stages. That supports the proposed change in trajectory, but the paper reports a significant later decline rather than a plateau. The tau PET comparison is attributed to a different citation and is not judged here; page numbers were not available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredProgression of biomarker measures in Alzheimer's disease is a continuous process that begins before symptoms.
“and that progression of biomarker measures is also a continuous process that begins before symptoms [9–14]”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [14]
In DIAN, CSF tau rises about 15 years before expected symptoms, earlier than baseline CSF NfL rises.
“In the DIAN cohort, the increase of tau in the CSF (absolute levels, cross-sectional) occurs as early as 15 years before the estimated age of symptom onset32, which is much earlier than the increase of base-line NfL in the CSF.”
From Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease (2019) · cites this paper as [32]
CSF tau levels are higher in AD than in controls, but the levels decrease as the disease progresses despite the accrual of NFTs.
“Although CSF tau levels are higher in AD than in controls, the levels decrease as the disease progresses, despite the accrual of NFTs56.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [56]
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References 102 · Cited by 434
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- Authors
- Fagan, A. M., Xiong, C., Jasielec, M. S., Bateman, R. J., Goate, A. M., Benzinger, T. L. S., Ghetti, B., Martins, R. N., Masters, C. L., Mayeux, R., Ringman, J. M., Rossor, M. N., Salloway, S., Schofield, P. R., Sperling, R. A., Marcus, D., Cairns, N. J., Buckles, V. D., Ladenson, J. H., Morris, J. C., Holtzman, D. M., & The Dominantly Inherited Alzheimer Network
- Affiliations
- Washington University in St. Louis (US)
- Indiana University Indianapolis (US)
- Edith Cowan University (AU)
- Mental Health Research Institute (AU)
- Columbia University (US)
- University of California, Los Angeles (US)
- University College London (GB)
- Brown University (US)
- UNSW Sydney (AU)
- Brigham and Women's Hospital (US)
- Corresponding author
- Fagan, Anne M.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2014-03-05
- Volume
- 6
- Issue
- 226
- Pages
- 226ra30-226ra30
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4038930
- OpenAlex
- W2096890121
- Cited by
- 434
- References
- 102
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 23 · 2023: 33 · 2022: 39 · 2021: 55 · 2020: 49 · 2019: 31 · 2018: 44 · 2017: 29 · 2016: 36 · 2015: 38 · 2014: 18
- FWCI
- 26.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Edith Cowan University Research Online (Edith Cowan University) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0512-10033)
- National Institute on Aging (R01AG016750, K24AG035007, P50-AG016750, U24 AG21886, UF1AG032438, P50AG005681, P01AG003991, P50AG005134, U19AG032438, U01AG032438, P01AG036694, P01AG026276, U24AG021886)
- National Institute of Neurological Disorders and Stroke (P30NS057105, P30NS048056, P30NS098577)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR048335)
- National Institute of Biomedical Imaging and Bioengineering (R01EB009352)
- National Center for Research Resources (KL2RR024994)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- autosomal dominant Alzheimer's disease, cerebrospinal fluid biomarkers, amyloid-beta 42, tau protein, phosphorylated tau 181, VILIP-1, preclinical Alzheimer's disease, amyloid plaques, neurofibrillary tangles, age at symptom onset, longitudinal biomarker trajectories, amyloid imaging
- MeSH terms
- Adult, Alleles, Alzheimer Disease, Cognition, Cross-Sectional Studies, Female, Genes, Dominant, Homozygote, Humans, Immunoassay, Male, Middle Aged, Mutation, Peptide Fragments, Phosphorylation, Time Factors, Cohort Studies, Biomarkers, Amyloid beta-Peptides, Disease Progression, Positron-Emission Tomography
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