Cerebrospinal Fluid β-Amyloid 42 and Tau Proteins as Biomarkers of Alzheimer-Type Pathologic Changes in the Brain
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BACKGROUND: There is a clear need to develop an objective diagnostic test for Alzheimer disease (AD). Changes in the levels of cerebrospinal fluid (CSF) tau protein and beta-amyloid 42 (Abeta42) peptide in patients with AD have been well documented, but the relationship between these biomarkers and neuropathologic changes in the brain is not established. OBJECTIVE: To study the relationship between antemortem CSF biomarker levels and Alzheimer-type neuropathologic changes in the brain. DESIGN: Cross-sectional study to correlate levels of CSF Abeta42, total tau, and phosphorylated tau protein with neuropathologic changes in the brain. SETTING: Academic research. Patients The study included 123 patients (79 with clinically diagnosed AD, 29 with other dementia, and 15 with other neurologic disease). All underwent clinical evaluation and provided antemortem lumbar CSF samples, and neuropathologic data were collected from September 11, 1990, to March 13, 2003, in the Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. MAIN OUTCOME MEASURES: Levels of CSF Abeta42, total tau, and phosphorylated tau protein were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Abeta, hyperphosphorylated tau, and alpha-synuclein. RESULTS: Cerebrospinal fluid Abeta42 and tau protein levels were related to amyloid load and the presence of neurofibrillary pathologic abnormalities in the brain. Cerebrospinal fluid Abeta42 level correlated inversely with total Abeta load in the brain, and CSF tau level correlated with results of immunohistochemistry for hyperphosphorylated tau and with the presence of neocortical neurofibrillary tangles. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Abeta42 level and of increased CSF tau level. Based on the ratio of phosphorylated tau level to Abeta42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of pathologic neuritic plaque in the brain. CONCLUSIONS: Cerebrospinal fluid Abeta42 and tau proteins are biomarkers of AD-associated pathologic changes in the brain. The combination of abnormally low CSF Abeta42 level and abnormally high CSF tau level predicted the presence of AD pathologic features with high accuracy. This combination assay may be helpful in diagnosing the presence of AD pathologic changes in the brain.
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A CSF biomarker profile defined by reduced levels of Aβ42 in conjunction with elevated t-tau and p-tau provides a robust biochemical signature for detecting AD pathology and distinguishing it from other neurodegenerative disorders.
“A characteristic biomarker profile, defined by reduced levels of Aβ42 in conjunction with elevated t-tau and p-tau, provides a robust biochemical signature for detecting AD pathology and distinguishing it from other neurodegenerative disorders72,73.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [73]
The COMMENT section reports that low CSF Aβ42 with high tau predicts AD-associated pathology with high accuracy, and the COMBINATION OF Aβ42 AND TAU section finds discrimination between high-probability AD and low-probability or other pathology. The paper also reports strong discrimination for the p-tau/Aβ42 ratio, but it does not establish the claimed profile requiring elevated total tau and p-tau together or its ability to distinguish AD from neurodegenerative disorders generally. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA CSF Aβ42 concentration lower than 500 pg/mL has been utilized as a reliable threshold for the presence of cerebral Aβ deposition in humans.
“Given that a CSF Aβ42 concentration lower than 500 pg/mL has been utilized as a reliable threshold for the presence of cerebral Aβ deposition in humans (7, 19, 22, 26)”
From Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance (2011) · cites this paper as [26]
The CSF Biomarker Levels and Amyloid Pathologic Changes section reports that lower CSF Aβ42 was associated with greater cerebral amyloid burden, but gives 515 pg/mL—not 500 pg/mL—as the optimum cutoff for pathologic neuritic plaques. The Comment section cautions that this cutoff was valid only in the study group and required independent validation, so the paper does not establish it as a reliable threshold in humans generally. Page numbers were not provided in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredThe level of CSF P-tau correlates with severity of PHF tau accumulation after death.
“The level of CSF P-tau also does correlate with severity of PHF tau accumulation after death [81,150].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [150]
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- Authors
- Tapiola, T., Alafuzoff, I., Herukka, S.-K., Parkkinen, L., Hartikainen, P., Soininen, H., & Pirttilä, T.
- Affiliations
- University of Eastern Finland (FI)
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2009-03-01
- Volume
- 66
- Issue
- 3
- Pages
- 382-9
- ISSN
- 0003-9942 (ISSN-L)
- OpenAlex
- W2075193321
- Cited by
- 896
- References
- 29
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 45 · 2023: 27 · 2022: 34 · 2021: 78 · 2020: 89 · 2019: 75 · 2018: 60 · 2017: 59 · 2016: 51 · 2015: 65 · 2014: 48 · 2013: 63 · 2012: 41
- FWCI
- 32.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Kuopion Yliopistollinen Sairaala
- 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, tau protein, phosphorylated tau, amyloid plaques, neurofibrillary tangles, diagnostic accuracy, lumbar CSF, neurodegeneration, alpha-synuclein, postmortem neuropathology, biomarker ratios, sensitivity and specificity
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Cross-Sectional Studies, Dementia, Female, Humans, Immunoassay, Male, Nervous System Diseases, Peptide Fragments, Retrospective Studies, ROC Curve, Logistic Models, Amyloid beta-Peptides, Silver Staining, tau Proteins, Statistics, Nonparametric, Plaque, Amyloid
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