Predicting Reduction of Cerebrospinal Fluid β-Amyloid 42 in Cognitively Healthy Controls
Abstract
IMPORTANCE: Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation without symptoms. Several trials focus on this stage and use biomarkers to include Aβ-positive participants, but an even earlier prevention of Aβ accumulation may be an effective treatment strategy. OBJECTIVE: To determine whether people who appear to be Aβ negative but are at high risk for Aβ positivity within the near future can be identified. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal biomarker cohort study involving 35 cognitively healthy individuals who underwent cerebrospinal fluid (CSF) sampling for up to 3 years during the study (October 24, 2005, to September 1, 2014). All participants had normal CSF Aβ42 levels at baseline. MAIN OUTCOMES AND MEASURES: Predictors of future Aβ positivity (levels of CSF Aβ42 declining below a previously validated cutoff level of 192 ng/L) tested by random forest models. Tested predictors included levels of protein in the CSF, hippocampal volume, genetics, demographics, and cognitive scores. RESULTS: The CSF Aβ42 levels declined in 11 participants, and the CSF became Aβ positive. The baseline CSF Aβ42 level was a strong predictor of future positivity (accuracy, 79% [95% CI, 70%-87%]). Ten of 11 decliners had baseline CSF Aβ42 levels in the lower tertile of the reference range (<225 ng/L), and 22 of 24 nondecliners had baseline CSF Aβ42 levels in the upper 2 tertiles (≥225 ng/L). A high CSF P-tau level was associated with decline (accuracy, 68%; 95% CI, 55%-81%). CONCLUSIONS AND RELEVANCE: Baseline CSF Aβ42 levels in the lower part of the reference range are strongly associated with future Aβ positivity. This finding can be used in trials on very early prevention of Alzheimer disease to identify people at high risk for Aβ accumulation as defined by low CSF Aβ42 levels.
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Those with low levels of CSF Aβ42, but still within the normal range, have a high risk of becoming abnormal within the next couple of years.
“Those with low levels of CSF Aβ42, but still within the normal range, have a high risk of becoming abnormal within the next couple of years13, which suggests that sub-threshold CSF Aβ42 levels indicate very early Aβ accumulation.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [13]
Sub-threshold CSF Aβ42 levels indicate very early Aβ accumulation.
“Those with low levels of CSF Aβ42, but still within the normal range, have a high risk of becoming abnormal within the next couple of years13, which suggests that sub-threshold CSF Aβ42 levels indicate very early Aβ accumulation.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [13]
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Plasma Aβ42/40 predicts progression from Aβ-amyloid negative to positive PET scans
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- Authors
- Mattsson, N., Insel, P. S., Donohue, M., Jagust, W., Sperling, R., Aisen, P., & Weiner, M. W.
- Affiliations
- San Francisco VA Medical Center (US)
- University of California San Diego (US)
- University of California, Berkeley (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Mattsson, Niklas
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2015-05-01
- Volume
- 72
- Issue
- 5
- Pages
- 554
- ISSN
- 2168-6149 (ISSN-L)
- OpenAlex
- W2013565978
- Cited by
- 45
- References
- 43
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 6 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 8 · 2016: 9 · 2015: 6
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5u01ag024904-10)
- National Institute on Aging (U01-AG-024904)
- 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, preclinical Alzheimer's disease, amyloid accumulation, risk prediction, cerebrospinal fluid biomarkers, phosphorylated tau, hippocampal volume, random forest
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Longitudinal Studies, Male, Peptide Fragments, Prognosis, Reference Values, Biomarkers, Amyloid beta-Peptides, Prodromal Symptoms
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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