Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ 42 in humans
Abstract
OBJECTIVES: Amyloid-beta(42) (Abeta(42)) appears central to Alzheimer's disease (AD) pathogenesis and is a major component of amyloid plaques. Mean cerebrospinal fluid (CSF) Abeta(42) is decreased in dementia of the Alzheimer's type. This decrease may reflect plaques acting as an Abeta(42) "sink," hindering transport of soluble Abeta(42) between brain and CSF. We investigated this hypothesis. METHODS: We compared the in vivo brain amyloid load (via positron emission tomography imaging of the amyloid-binding agent, Pittsburgh Compound-B [PIB]) with CSF Abeta(42) and other measures (via enzyme-linked immunosorbent assay) in clinically characterized research subjects. RESULTS: Subjects fell into two nonoverlapping groups: those with positive PIB binding had the lowest CSF Abeta(42) level, and those with negative PIB binding had the highest CSF Abeta(42) level. No relation was observed between PIB binding and CSF Abeta(40), tau, phospho-tau(181), plasma Abeta(40), or plasma Abeta(42). Importantly, PIB binding and CSF Abeta(42) did not consistently correspond with clinical diagnosis; three cognitively normal subjects were PIB-positive with low CSF Abeta(42), suggesting the presence of amyloid in the absence of cognitive impairment (ie, preclinical AD). INTERPRETATION: These observations suggest that brain amyloid deposition results in low CSF Abeta(42), and that amyloid imaging and CSF Abeta(42) may potentially serve as antecedent biomarkers of (preclinical) AD.
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The continuous relationship between CSF Aβ42 and amyloid PET is "L-shaped" rather than linear.
“The continuous relationship between CSF Aβ42 and amyloid PET, however, is “L-shaped” rather than linear [116,117,120].”
From NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease (2018) · cites this paper as [120]
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 [18]
People with brain amyloid deposition have low CSF Aβ42.
“Since people with brain amyloid deposition have low CSF Aβ42 (Fagan et al., 2006), this strongly suggests that amyloid deposition on average is beginning earlier in apoE4-positive subjects.”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Fagan et al., 2006
The lower CSF Aβ42 in apoE4-positive cognitively normal middle age people strongly suggests that amyloid deposition on average is beginning earlier in apoE4-positive subjects.
“Since people with brain amyloid deposition have low CSF Aβ42 (Fagan et al., 2006), this strongly suggests that amyloid deposition on average is beginning earlier in apoE4-positive subjects.”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Fagan et al., 2006
Antemortem AD diagnosis relies heavily on the presence of Aβ and tau, either measured in spinal fluid or imaged using positron emission tomography.
“Antemortem diagnosis also relies heavily on the presence of Aβ and tau, either as measured in the spinal fluid or imaged using positron emission tomography (PET) [7–10].”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [9]
CSF Aβ42 levels are typically reduced in dementia of the Alzheimer type (DAT), reflecting its aggregation and deposition as amyloid in the brain.
“Levels of CSF Aβ42 are typically reduced in dementia of the Alzheimer type (DAT),8-11 reflecting its aggregation and deposition as amyloid in the brain,12”
From Decreased cerebrospinal fluid Aβ <sub>42</sub> correlates with brain atrophy in cognitively normal elderly (2009) · cites this paper as [12]
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“icant neuronal loss in vulnerable regions, such as the entorhinal cortex.(19) However, cognitively normal individuals with neuropathological AD (preclinical AD) do not demonstrate such neuronal loss,(20) and we observed reduced CSF A 42 levels in three cognitively normal subjects.”
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- Authors
- Fagan, A. M., Mintun, M. A., Mach, R. H., Lee, S., Dence, C. S., Shah, A. R., LaRossa, G. N., Spinner, M. L., Klunk, W. E., Mathis, C. A., DeKosky, S. T., Morris, J. C., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- University of Pittsburgh (US)
- Corresponding author
- Fagan, Anne M.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2006-02-17
- Volume
- 59
- Issue
- 3
- Pages
- 512-519
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2006858320
- Cited by
- 1,246
- References
- 5
- Citations by year
- 2026: 16 · 2025: 30 · 2024: 37 · 2023: 35 · 2022: 40 · 2021: 45 · 2020: 77 · 2019: 56 · 2018: 50 · 2017: 67 · 2016: 71 · 2015: 69 · 2014: 65 · 2013: 94 · 2012: 76
- FWCI
- 27.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG03991, AG 05681, AG026276, P50AG005681, P01AG003991, P01AG026276)
- National Institute of Neurological Disorders and Stroke (P30NS048056)
- National Center for Research Resources (M01-RR00036, M01RR000036)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Keywords
- amyloid-beta 42, cerebrospinal fluid biomarkers, Pittsburgh compound B, amyloid plaques, Alzheimer's disease, preclinical Alzheimer's disease, amyloid imaging, tau protein, phosphorylated tau, plasma amyloid-beta, cognitive impairment
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Diagnostic Imaging, Female, Humans, Image Processing, Computer-Assisted, Male, Memory, Middle Aged, Neuropsychological Tests, Peptide Fragments, Tissue Distribution, Amyloid beta-Peptides
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