Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects
Open accessAbstract
Objective: Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Methods: Amyloid‐β 1 to 42 peptide (Aβ 1–42), total tau (t‐tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy‐confirmed AD cases and 52 age‐matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t‐tau and Aβ 1–42 in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy‐confirmed CSF data. Results: CSF Aβ 1–42 was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for Aβ 1–42, t‐tau, and APO ε 4 allele count provided the best assessment delineation of mild AD. An AD‐like baseline CSF profile for t‐tau/Aβ 1–42 was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. Interpretation: The CSF biomarker signature of AD defined by Aβ 1–42 and t‐tau in the autopsy‐confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD. Ann Neurol 2009
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PIB uptake and CSF Aβ42 are reliable surrogate markers of amyloid plaque pathology in living subjects.
“A preponderance of evidence supports the interpretation that PIB uptake and CSF Aβ42 are reliable surrogate markers of amyloid plaque pathology in living subjects (15-19).”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [17]
The Interpretation section links reduced CSF Aβ1-42 to amyloid accumulation in brain plaques, and the Discussion reports that CSF Aβ1-42 was the most sensitive single AD biomarker in the studied cohorts. The paper mentions Pittsburgh compound B imaging in Subjects and Methods but does not establish that PIB uptake is a reliable surrogate for plaque pathology. Page numbers are not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIncreased concentrations of extracellular soluble p-tau and t-tau constitute a reliable index of the intracellular NFT process in MCI due to AD and AD dementia.
“Increased concentrations of extracellular soluble phosphorylated tau (p-tau) and total tau (t-tau) constitute a reliable index of this intracellular process in mild cognitive impairment due to AD2,3 and AD dementia.2,4”
From Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer's disease (2022) · cites this paper as [4]
The Results report higher CSF p-tau and t-tau in MCI than in cognitively normal subjects, with further increases in AD. The Interpretation links CSF tau to neurons that harbor tangles, but describes that link as a proposed explanation and identifies tau together with reduced Aβ1-42—not tau alone—as the diagnostic biomarker signature. It does not establish that elevated soluble tau is a reliable index of the intracellular NFT process in either group. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAbnormal CSF Aβ42 values were defined using the previously established cut-off of <192 ng/L.
“Abnormal CSF Aβ42 values were defined using the previously established cut-off of <192 ng/L57–59.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [57]
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- Authors
- Shaw, L. M., Vanderstichele, H., Knapik‐Czajka, M., Clark, C. M., Aisen, P. S., Petersen, R. C., Blennow, K., Soares, H., Simon, A., Lewczuk, P., Dean, R., Siemers, E., Potter, W., Lee, V. M. ‐., Trojanowski, J. Q., & Initiative, A. D. N.
- Affiliations
- University of Pennsylvania (US)
- Fujirebio (Belgium) (BE)
- University of California San Diego (US)
- Mayo Clinic (US)
- University of Gothenburg (SE)
- Pfizer (United States) (US)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Eli Lilly (United States) (US)
- Corresponding author
- Shaw, Leslie M.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2009-04
- Volume
- 65
- Issue
- 4
- Pages
- 403-413
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC2696350
- OpenAlex
- W2008301592
- Cited by
- 2,065
- References
- 31
- Citations by year
- 2026: 59 · 2025: 82 · 2024: 110 · 2023: 89 · 2022: 114 · 2021: 125 · 2020: 136 · 2019: 141 · 2018: 129 · 2017: 135 · 2016: 121 · 2015: 146 · 2014: 131 · 2013: 130 · 2012: 136
- FWCI
- 85.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health (5u01ag024904-10)
- National Institute on Aging (U01-AG-024904, AG 024904, P30AG010124, AG-10124, U19AG010483, U19AG024904)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- Alzheimer's disease, cerebrospinal fluid biomarkers, amyloid-beta 42, total tau, mild cognitive impairment, conversion to Alzheimer's disease, APOE ε4, Alzheimer's Disease Neuroimaging Initiative
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cognition Disorders, Diagnostic Imaging, Female, Humans, Male, Middle Aged, Peptide Fragments, Phosphorylation, Retrospective Studies, ROC Curve, Sensitivity and Specificity, Threonine, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Disease Progression, Statistics, Nonparametric, Area Under Curve, Apolipoprotein E4
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