Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People
Open accessAbstract
OBJECTIVE: To identify biomarker patterns typical for Alzheimer disease (AD) in an independent, unsupervised way, without using information on the clinical diagnosis. DESIGN: Mixture modeling approach. SETTING: Alzheimer's Disease Neuroimaging Initiative database. PATIENTS OR OTHER PARTICIPANTS: Cognitively normal persons, patients with AD, and individuals with mild cognitive impairment. MAIN OUTCOME MEASURES: Cerebrospinal fluid-derived beta-amyloid protein 1-42, total tau protein, and phosphorylated tau(181P) protein concentrations were used as biomarkers on a clinically well-characterized data set. The outcome of the qualification analysis was validated on 2 additional data sets, 1 of which was autopsy confirmed. RESULTS: Using the US Alzheimer's Disease Neuroimaging Initiative data set, a cerebrospinal fluid beta-amyloid protein 1-42/phosphorylated tau(181P) biomarker mixture model identified 1 feature linked to AD, while the other matched the "healthy" status. The AD signature was found in 90%, 72%, and 36% of patients in the AD, mild cognitive impairment, and cognitively normal groups, respectively. The cognitively normal group with the AD signature was enriched in apolipoprotein E epsilon4 allele carriers. Results were validated on 2 other data sets. In 1 study consisting of 68 autopsy-confirmed AD cases, 64 of 68 patients (94% sensitivity) were correctly classified with the AD feature. In another data set with patients (n = 57) with mild cognitive impairment followed up for 5 years, the model showed a sensitivity of 100% in patients progressing to AD. CONCLUSIONS: The mixture modeling approach, totally independent of clinical AD diagnosis, correctly classified patients with AD. The unexpected presence of the AD signature in more than one-third of cognitively normal subjects suggests that AD pathology is active and detectable earlier than has heretofore been envisioned.
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Abnormal CSF Aβ42 values were defined using the previously established cut-off of <192 ng/L.
“Abnormal CSF Aβ42 values were defined using the previously established cut-off of <192 ng/L57–59.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [58]
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- Authors
- De Meyer, G.
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2010-08-01
- Volume
- 67
- Issue
- 8
- Pages
- 949
- ISSN
- 0003-9942 (ISSN-L)
- PMC
- PMC2963067
- OpenAlex
- W2141854336
- Cited by
- 462
- References
- 24
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 14 · 2023: 8 · 2022: 13 · 2021: 18 · 2020: 43 · 2019: 16 · 2018: 19 · 2017: 24 · 2016: 15 · 2015: 31 · 2014: 44 · 2013: 35 · 2012: 58
- FWCI
- 42.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- National Institutes of Health (5u01ag024904-10)
- National Institute on Aging (U01-AG-024904, P30AG010124, U19AG010483)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- Alzheimer's disease, biomarker signatures, cerebrospinal fluid, amyloid-beta 42, phosphorylated tau, total tau, mixture models, cognitively normal elderly, mild cognitive impairment, APOE ε4, unsupervised classification
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cognition, Female, Follow-Up Studies, Humans, Male, Peptide Fragments, ROC Curve, Reproducibility of Results, Biomarkers, Geriatric Assessment, Amyloid beta-Peptides, tau Proteins, Apolipoprotein E4
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