Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease
Open accessAbstract
Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-beta(42) (Abeta(42)) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau(181) (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Abeta(42) but not for plasma Abeta species. Some individuals have low CSF Abeta(42) but no cortical PIB binding. Together, these data suggest that changes in brain Abeta(42) metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Abeta(42) initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.
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Aβ42 levels decrease in the CSF as Aβ starts to accumulate, before fibrillar plaques can be detected with PET.
“Previous cross-sectional studies indicate that Aβ42 levels decrease in the CSF as Aβ starts to accumulate, before fibrillar plaques can be detected with PET7–11.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [9]
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Self-citation
- Authors
- Fagan, A. M., Mintun, M. A., Shah, A. R., Aldea, P., Roe, C. M., Mach, R. H., Marcus, D., Morris, J. C., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Fagan, Anne M.
- Venue
- EMBO Molecular Medicine
- Published
- 2009-11-26
- Volume
- 1
- Issue
- 8-9
- Pages
- 371-380
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC2806678
- OpenAlex
- W2166207589
- Cited by
- 353
- References
- 50
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 8 · 2023: 18 · 2022: 14 · 2021: 26 · 2020: 21 · 2019: 18 · 2018: 15 · 2017: 18 · 2016: 28 · 2015: 21 · 2014: 28 · 2013: 34 · 2012: 23
- FWCI
- 17.45
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Aging of the National Institutes of Health (P50 AG05681, P01 AG03991, P01 AG026276, P30 NS057105)
- National Institute of Neurological Disorders and Stroke (P30 NS048056)
- National Center for Research Resources, NIH Roadmap for Medical Research (UL1 RR024992)
- Dana Foundation
- Charles and Joanne Knight Alzheimer Research Initiative
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- Alzheimer's disease, cerebrospinal fluid tau, phosphorylated tau, p-tau181, cortical amyloid deposition, amyloid-beta 42, Pittsburgh compound B, neurofibrillary tangles, preclinical Alzheimer's disease, cerebrospinal fluid biomarkers, amyloid-beta metabolism, plasma amyloid-beta, early diagnosis, inclusion and exclusion criteria
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Aniline Compounds, Cerebellar Cortex, Female, Humans, Male, Middle Aged, Protein Binding, Thiazoles, Amyloid beta-Peptides, Neurofibrillary Tangles, Positron-Emission Tomography
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