Phosphorylated Tau-Aβ42 Ratio as a Continuous Trait for Biomarker Discovery for Early-Stage Alzheimer’s Disease in Multiplex Immunoassay Panels of Cerebrospinal Fluid
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Background Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome.Methods A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses.Results The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD.Conclusions Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.
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The CSF tau/Aβ ratio is a powerful predictor of cognitive decline and can distinguish vascular dementia from Alzheimer's disease.
“We hypothesized that CLU levels were also associated with CSF tau/Aβ ratio, a powerful predictor of cognitive decline that can be used to discriminate between vascular dementia and AD (de Jong, et al., 2006,Fagan, et al., 2007,Harari, et al., 2014)”
From A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin (2016) · cites this paper as Harari, et al., 2014
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- Authors
- Harari, O., Cruchaga, C., Kauwe, J. S. K., Ainscough, B. J., Bales, K., Pickering, E. H., Bertelsen, S., Fagan, A. M., Holtzman, D. M., Morris, J. C., & Goate, A. M.
- Affiliations
- Washington University in St. Louis (US)
- Brigham Young University (US)
- Pfizer (United States) (US)
- Corresponding author
- Goate, Alison M.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 75
- Issue
- 9
- Pages
- 723-731
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4007142
- OpenAlex
- W2065398617
- Cited by
- 82
- References
- 39
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 7 · 2020: 10 · 2019: 6 · 2018: 7 · 2017: 12 · 2016: 4 · 2015: 9 · 2014: 1
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P30 NS069329-01, R01 AG035083, R01 AG16208, UL1 TR000448)
- Pfizer
- Foundation for Barnes-Jewish Hospital
- 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, early Alzheimer's disease, cerebrospinal fluid biomarkers, phosphorylated tau, amyloid-beta 42, heart-type fatty acid-binding protein, multiplex immunoassay, disease transformation, disease progression
- MeSH terms
- Fatty Acid Binding Protein 3, Aged, 80 and over, Alzheimer Disease, Female, Humans, Immunoassay, Macrophage Migration-Inhibitory Factors, Male, Peptide Fragments, Phosphorylation, Time Factors, Cohort Studies, Biomarkers, Multivariate Analysis, Case-Control Studies, Amyloid beta-Peptides, tau Proteins, Disease Progression, Intramolecular Oxidoreductases, Vascular Endothelial Growth Factor A, Fatty Acid-Binding Proteins, Kaplan-Meier Estimate
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