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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/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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Cites
The Elements of Statistical Learning
Hastie, T., Friedman, J., & Tibshirani, R. (2001) · Springer Series in Statistics · doi:10.1007/978-0-387-21606-5 · Cited by 24,162
Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria
Dubois, B., Feldman, H. H., Jacova, C., DeKosky, S. T., Barberger-Gateau, P., Cummings, J., Delacourte, A., Galasko, D., Gauthier, S., Jicha, G., et al. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70178-3 · Cited by 4,411
ROCR: visualizing classifier performance in R
Sing, T., Sander, O., Beerenwinkel, N., & Lengauer, T. (2005) · Computer applications in the biosciences · doi:10.1093/bioinformatics/bti623 · Cited by 3,172
Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects
Shaw, L. M., Vanderstichele, H., Knapik‐Czajka, M., Clark, C. M., Aisen, P. S., Petersen, R. C., Blennow, K., Soares, H., Simon, A., Lewczuk, P., et al. (2009) · Annals of Neurology · doi:10.1002/ana.21610 · Cited by 2,065
Hansson, O., Zetterberg, H., Buchhave, P., Londos, E., Blennow, K., & Minthon, L. (2006) · The Lancet Neurology · doi:10.1016/s1474-4422(06)70355-6 · Cited by 1,700
Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ 42 in humans
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., et al. (2006) · Annals of Neurology · doi:10.1002/ana.20730 · Cited by 1,246
Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins
Ray, S., Britschgi, M., Herbert, C., Takeda-Uchimura, Y., Boxer, A., Blennow, K., Friedman, L. F., Galasko, D. R., Jutel, M., Karydas, A., et al. (2007) · Nature Medicine · doi:10.1038/nm1653 · Cited by 1,048
Pike, K. E., Savage, G., Villemagne, V. L., Ng, S., Moss, S. A., Maruff, P., Mathis, C. A., Klunk, W. E., Masters, C. L., & Rowe, C. C. (2007) · Brain · doi:10.1093/brain/awm238 · Cited by 789
Improved discrimination of AD patients using β-amyloid (1-42) and tau levels in CSF
Hulstaert, F., Blennow, K., Ivanoiu, A., Schoonderwaldt, H. C., Riemenschneider, M., Deyn, P. P. D., Bancher, C., Cras, P., Wiltfang, J., Mehta, P. D., et al. (1999) · Neurology · doi:10.1212/wnl.52.8.1555 · Cited by 724
Two-year follow-up of amyloid deposition in patients with Alzheimer's disease
Engler, H., Forsberg, A., Almkvist, O., Blomquist, G., Larsson, E., Savitcheva, I., Wall, A. E., Ringheim, A., Långström, B., & Nordberg, A. K. (2006) · Brain · doi:10.1093/brain/awl178 · Cited by 614
Alzheimer neuropathologic alterations in aged cognitively normal subjects
Davis, D. G., Schmitt, F. A., Wekstein, D. R., & Markesbery, W. R. (1999) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199904000-00008 · Cited by 516 · cited 1×
“This is not surprising because many neuropathological studies on cognitively normal elderly individuals reveal that a large portion of healthy elderly individuals exhibit amyloid-containing plaques and taucontaining neurofibrillary tangles in their brains.(21,22) Moreover, Pittsburgh Compound B positron emission tomog…”
Olsson, A., Vanderstichele, H., Andreasen, N., Meyer, G. D., Wallin, A., Holmberg, B., Rosengren, L., Vanmechelen, E., & Blennow, K. (2004) · Clinical Chemistry · doi:10.1373/clinchem.2004.039347 · Cited by 431
Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics
Shaw, L. M. J., Korecka, M., Clark, C. M., Lee, V. M. ‐., & Trojanowski, J. Q. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2176 · Cited by 348
Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia
Engelborghs, S., de Vreese, K., de Casteele, T. V., Vanderstichele, H., Everbroeck, B. V., Cras, P. P., Martin, J., Vanmechelen, E., & Deyn, P. P. D. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.02.016 · Cited by 268
CSF biomarkers in frontotemporal lobar degeneration with known pathology
Bian, H., Van Swieten, J. C., Leight, S., Massimo, L., Wood, E., Forman, M., Moore, P., de Koning, I., Clark, C. M., Rosso, S., et al. (2008) · Neurology · doi:10.1212/01.wnl.0000311445.21321.fc · Cited by 216
Cerebrospinal fluid -amyloid 1-42 concentration may predict cognitive decline in older women
Gustafson, D. R., Skoog, I., Rosengren, L., Zetterberg, H., & Blennow, K. (2006) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.2006.100529 · Cited by 214
Skoog, I., Davidsson, P., Aevarsson, Ó., Vanderstichele, H., Vanmechelen, E., & Blennow, K. (2003) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000068478 · Cited by 194
Summarizing the goodness of fit of generalized linear models for longitudinal data
Zheng, B. (2000) · Statistics in Medicine · doi:10.1002/(sici)1097-0258(20000530)19:10 · Cited by 194
Fitting finite mixtures of generalized linear regressions in R
Grün, B., & Leisch, F. (2006) · Computational Statistics & Data Analysis · doi:10.1016/j.csda.2006.08.014 · Cited by 190
Stomrud, E., Hansson, O., Blennow, K., Minthon, L., & Londos, E. (2007) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000105017 · Cited by 170
Peskind, E. R., Li, G., Shofer, J., Quinn, J. F., Kaye, J. A., Clark, C. M., Farlow, M. R., DeCarli, C., Raskind, M. A., Schellenberg, G. D., et al. (2006) · Archives of Neurology · doi:10.1001/archneur.63.7.936 · Cited by 131
Farrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124
Kauwe, J. S. K., Cruchaga, C., Mayo, K., Fenoglio, C., Bertelsen, S. E., Nowotny, P., Galimberti, D., Scarpini, E. A., Morris, J. C., Fagan, A. M., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801227105 · Cited by 90
Increasing CSF phospho-tau levels during cognitive decline and progression to dementia
Andersson, C., Blennow, K., Almkvist, O., Andreasen, N., Engfeldt, P., Johansson, S., Lindau, M. P., & Eriksdotter, M. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.03.027 · Cited by 65
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Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., Iwatsubo, T., Jack, C. R., Kaye, J., Montine, T. J., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.003 · Cited by 7,155
Karran, E., Mercken, M., & Strooper, B. D. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3505 · Cited by 2,188
A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Feldman, H. H., Frisoni, G. B., Hampel, H., Jagust, W. J., Johnson, K. A., Knopman, D. S., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002923 · Cited by 1,864
Petersen, R. C. (2011) · New England Journal of Medicine · doi:10.1056/nejmcp0910237 · Cited by 1,289
The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception
Weiner, M. W., Veitch, D. P., Aisen, P. S. S., Beckett, L. A., Cairns, N. J., Green, R. C., Harvey, D. J., Jack, C. R., Jagust, W. J., Liu, E., et al. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.05.1769 · Cited by 1,033
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Oncology › 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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