CSF A β 42/A β 40 and A β 42/A β 38 ratios: better diagnostic markers of Alzheimer disease
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Objective: The diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF A β 42/A β 40 and A β 42/A β 38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF A β 42 alone. Methods: The study comprised three different cohorts (n = 1182) in whom CSF levels of A β 42, A β 40, and A β 38 were assessed. CSF A β s were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid (18 F‐flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well‐characterized patients. Results: When using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF A β 42/A β 40 and A β 42/A β 38 ratios were significantly better predictors of abnormal amyloid PET than CSF A β 42. Lower A β 42, A β 42/A β 40, and A β 42/A β 38 ratios, but not A β 40 and A β 38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower A β 38, A β 40, and A β 42, but not the ratios, correlated with non‐AD‐specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the A β 42/A β 40 and A β 42/A β 38 ratios showed increased accuracy compared to A β 42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all A β s (including A β 42) were decreased. Interpretation: The CSF A β 42/A β 40 and A β 42/A β 38 ratios are significantly better than CSF A β 42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non‐AD dementias. The ratios reflect AD‐type pathology better, whereas decline in CSF A β 42 is also associated with non‐AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF A β 42 should be used in the clinical work‐up of AD.
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Study participants were categorized into normal (Aβ−) and pathologic (Aβ+) CSF signature using the CSF Aβ42/Aβ40 ratio cutoff ≤0.1.
“Study participants were categorized into groups with normal (Aβ−) and pathologic (Aβ+) CSF signature using the CSF Aβ42/Aβ40 ratio cutoff ≤0.1.16”
From CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease (2018) · cites this paper as [16]
The CSF Aβ42/Aβ40 ratio was used to define Aβ status, with a previously defined cut point (<0.1) to define positivity.
“The CSF Aβ42/Aβ40 ratio (using EUROIMMUN data) was used to define Aβ status, with a previously defined cut point (<0.1) to define positivity (42).”
From Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer's disease (2020) · cites this paper as [42]
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Has the time arrived for cerebrospinal fluid biomarkers in psychiatric disorders?
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APP‐derived peptides reflect neurodegeneration in frontotemporal dementia
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Self-citation
- Authors
- Janelidze, S., Zetterberg, H., Mattsson, N., Palmqvist, S., Vanderstichele, H., Lindberg, O., van Westen, D., Stomrud, E., Minthon, L., Blennow, K., the Swedish BioFINDER study group, & Hansson, O.
- Affiliations
- Lund University (SE)
- National Hospital for Neurology and Neurosurgery (GB)
- ADx NeuroSciences (BE)
- Department of Clinical Sciences Diagnostic Radiology Lund University Lund Sweden
- University of Gothenburg (SE)
- Corresponding author
- Janelidze, Shorena
- Hansson, Oskar
- ORCID
- Venue
- Annals of Clinical and Translational Neurology
- Publisher
- Wiley
- Published
- 2016-01
- Volume
- 3
- Issue
- 3
- Pages
- 154-165
- ISSN
- 2328-9503 (ISSN-L)
- PMC
- PMC4774260
- OpenAlex
- W2207877462
- Cited by
- 456
- References
- 49
- Citations by year
- 2026: 26 · 2025: 42 · 2024: 51 · 2023: 40 · 2022: 40 · 2021: 61 · 2020: 63 · 2019: 51 · 2018: 43 · 2017: 27 · 2016: 9
- FWCI
- 38.48
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Annals of Clinical and Translational Neurology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Chalmers Publication Library (Chalmers University of Technology) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- European Research Council
- Vetenskapsrådet
- Crafoordska Stiftelsen
- Hjärnfonden
- Torsten Söderbergs Stiftelse
- Knut och Alice Wallenbergs Stiftelse
- 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, Aβ40, Aβ42/Aβ40 ratio, prodromal Alzheimer's disease, mild cognitive impairment, subjective cognitive decline, amyloid PET, differential diagnosis of dementia, dementia with Lewy bodies, Parkinson's disease dementia, subcortical vascular dementia, hippocampal volume, white matter lesions, lateral ventricle, immunoassay comparison, diagnostic accuracy
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