Cited by 462Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsCancer-related cognitive impairment studies

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Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People

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De Meyer, Geert·2010·Archives of Neurology

DOI 10.1001/archneurol.2010.179PMC PMC2963067

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Abstract

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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Disease, Health, and Aging in the First Decade of the 21st CenturyDr. Siegler's work on this chapter was support by NIH Grant #R01 HL55356 from the National Heart Lung and Blood Institute (NHLBI) and cofunding by the National Institute on Aging (NIA); P01 HL36587, Grant #IIRG‐08‐89565 from the Alzheimer's Association and the Duke Behavioral Medicine Research Center.Dr. Elias' work on this chapter was supported by research grants 1RO1‐HL67358 and 1R01‐HL081290 from the NHLBI and The National Institutes of Health, to the University of Maine. The content is solely the responsibility of the author and does not represent the official views of the NHLBI.Dr. Bosworth's work on this chapter was supported by a NHLBI grant (R01 HL070713), a VA Health Services Research and Development grant (20‐034), an Established Investigator Award from the American Heart Association, and a VA Career Scientist Award(08‐027) to the third author. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs.Dr. Davey's work on this chapter has been supported by grants from the National Institute of Aging R01 AG13180, the National Cancer Institute R21CA158877, and from the U.S. Department of Agriculture PENR‐2008‐05011, PENR‐2010‐04643.We would like to thank Shirley Austin for her work on coordinating this chapter.We wish to acknowledge the editorial work by Ms. Danielle Briggeman, The University of Maine.
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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)
DOI: 10.1001/archneurol.2010.179
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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Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People

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