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Independent information from cerebrospinal fluid amyloid-β and florbetapir imaging in Alzheimer's disease
Open accessAbstract
Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal fluid total-tau and phosphorylated-tau levels (cross-sectionally); and hippocampal volume, fluorodeoxyglucose positron emission tomography results and Alzheimer's Disease Assessment Scale-cognitive subscale scores (longitudinally). Cerebrospinal fluid and positron emission tomography amyloid-β were highly correlated, but adjusting one of these predictors for the other revealed that they both provided partially independent information when predicting diagnosis, APOE ε4, hippocampal volume, metabolism, cognition, total-tau and phosphorylated-tau (the 95% confidence intervals of the adjusted effects did not include zero). Cerebrospinal fluid amyloid-β was more strongly related to APOE ε4 whereas positron emission tomography amyloid-β was more strongly related to tau levels (P < 0.05). Discordance (mainly isolated cerebrospinal fluid amyloid-β positivity) differed by diagnostic group (P < 0.001) and was seen in 21% of cognitively healthy people but only 6% in dementia patients. The finding that cerebrospinal fluid and positron emission tomography amyloid-β provide partially independent information about a wide range of Alzheimer's measures supports the theory that these modalities represent partly different aspects of Alzheimer's pathology. The fact that mismatch, with positive cerebrospinal fluid amyloid-β but normal positron emission tomography amyloid-β, is relatively common in cognitively healthy people may be considered when using these biomarkers to identify early stage Alzheimer's disease. Reduced cerebrospinal fluid amyloid-β may be more strongly related to early stage Alzheimer's disease, whereas increased positron emission tomography amyloid-β may be more strongly related to disease progression.
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“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 [10]
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“This may be due to a temporal offset between these two measures [121–123].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [121]
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NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.02.018 · Cited by 10,537
Self-citationThe Amyloid-β Pathway in Alzheimer’s Disease
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Self-citationPreclinical Alzheimer’s Disease: Definition, Natural History, and Diagnostic Criteria
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Self-citationBiomarkers for Alzheimer's disease: current status and prospects for the future
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Metadata
- Authors
- Mattsson, N., Insel, P. S., Donohue, M., Landau, S., Jagust, W. J., Shaw, L. M., Trojanowski, J. Q., Zetterberg, H., Blennow, K., & Weiner, M. W.
- Affiliations
- San Francisco VA Medical Center (US)
- University of California San Diego (US)
- University of California, Berkeley (US)
- University of Pennsylvania (US)
- National Hospital for Neurology and Neurosurgery (GB)
- University of Gothenburg (SE)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-12-24
- Volume
- 138
- Issue
- 3
- Pages
- 772-783
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC4339769
- OpenAlex
- W2103861278
- Cited by
- 237
- References
- 60
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 15 · 2023: 12 · 2022: 15 · 2021: 27 · 2020: 25 · 2019: 35 · 2018: 21 · 2017: 23 · 2016: 21 · 2015: 21
- FWCI
- 16.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Foundation for the National Institutes of Health (P30AG010129, K01 AG030514, U01AG024904, Grant U01 AG024904, AG024904)
- Alzheimer's Association (AG010129, U01 AG024904)
- Bristol-Myers Squibb (U01 AG024904, AG024904)
- Eli Lilly and Company (U01 AG024904, AG024904)
- Pfizer (AG024904, U01 AG024904)
- AstraZeneca
- Novartis
- F. Hoffmann-La Roche (AG024904, U01 AG024904)
- Medpace (U01 AG024904)
- Synarc (U01 AG024904, P30 AG010129, K01 AG030514)
- Alzheimer's Disease Neuroimaging Initiative (U01AG024904, AG024904, P30 AG010129, K01 AG030514)
- Northern California Institute for Research and Education (U01 AG024904, K01 AG030514, P30 AG010129)
- Elan (U01 AG024904)
- Eisai (U01 AG024904, AG024904)
- Vetenskapsrådet
- Sahlgrenska Universitetssjukhuset
- National Institutes of Health (5u01ag024904-10, U01-AG024904, Grant U01 AG024904, P30 AG010129 and K01 AG030514, AG010129, AG024904)
- U.S. Food and Drug Administration
- Genentech (AG024904, U01 AG024904)
- University of California, Los Angeles
- University of California, San Diego
- National Institute on Aging (U01-AG-024904, P30AG010129, AG 024904, K01AG030514, AG010129)
- National Institute of Biomedical Imaging and Bioengineering (U01 AG024904, AG024904)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- Alzheimer's disease, amyloid-beta, florbetapir PET, amyloid PET, biomarker discordance, APOE ε4, tau protein, phosphorylated tau, hippocampal volume, cerebral blood flow, FDG-PET, mild cognitive impairment, subjective memory complaints, Alzheimer's disease diagnosis
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Aniline Compounds, Cognition Disorders, Ethylene Glycols, Female, Fluorine Radioisotopes, Humans, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Peptide Fragments, Cohort Studies, Amyloid beta-Peptides, Fluorodeoxyglucose F18, Positron-Emission Tomography, Apolipoprotein E4
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