High Cerebrospinal Fluid Tau and Low Amyloid β42 Levels in the Clinical Diagnosis of Alzheimer Disease and Relation to Apolipoprotein E Genotype
Abstract
OBJECTIVE: To evaluate cerebrospinal fluid (CSF) levels of amyloid beta protein ending at amino acid 42 (Abeta42) and tau as markers for Alzheimer disease (AD) and to determine whether clinical variables influence these levels. DESIGN: Cohort study. SETTING: Six academic research centers with expertise in dementia. SUBJECTS: Eighty-two patients with probable AD, including 24 with very mild dementia (Mini-Mental State Examination score >23/30) (AD group); 60 cognitively normal elderly control subjects (NC group); and 74 subjects with neurological disorders, including dementia (ND group). MAIN OUTCOME MEASURES: Levels of Abeta42 and tau were compared among AD, NC, and ND groups. Relationships of age, sex, Mini-Mental State Examination score, and apolipoprotein E (Apo E) genotype with these levels were examined using multiple linear regression. Classification tree models were developed to optimize distinguishing AD from NC groups. RESULTS: Levels of Abeta42 were significantly lower, and levels of tau were significantly higher, in the AD group than in the NC or ND group. In the AD group, Abeta42 level was inversely associated with Apo E epsilon4 allele dose and weakly related to Mini-Mental State Examination score; tau level was associated with male sex and 1 Apo E epsilon4 allele. Classification tree analysis, comparing the AD and NC subjects, was 90% sensitive and 80% specific. With specificity set at greater than 90%, the tree was 77% sensitive for AD. This tree classified 26 of 74 members of the ND group as having AD. They had diagnoses difficult to distinguish from AD clinically and a high Apo E epsilon4 allele frequency. Markers in CSF were used to correctly classify 12 of 13 patients who later underwent autopsy, including 1 with AD not diagnosed clinically. CONCLUSIONS: Levels of CSF Abeta42 decrease and levels of CSF tau increase in AD. Apolipoprotein E epsilon4 had a dose-dependent relationship with CSF levels of Abeta42, but not tau. Other covariates influenced CSF markers minimally. Combined analysis of CSF Abeta42 and tau levels discriminated patients with AD, including patients with mild dementia, from the NC group, supporting use of these proteins to identify AD and to distinguish early AD from aging. In subjects in the ND group with an AD CSF profile, autopsy follow-up will be required to decide whether CSF results are false positive, or whether AD is a primary or concomitant cause of dementia.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [9]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Validation of clinical diagnostic criteria for Alzheimer's disease
Morris, J. C., McKeel, D. W., Fulling, K., Torack, R. M., & Berg, L. (1988) · Annals of Neurology · doi:10.1002/ana.410240105 · Cited by 362 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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 · see citing works
Self-citationSoluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease
Lue, L.-F., Kuo, Y.-M., Roher, A. E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., & Rogers, J. (1999) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65184-x · Cited by 1,530 · see citing works
Knopman, D. S., DeKosky, S. T., Cummings, J. L., Chui, H., Corey–Bloom, J., Relkin, N., Small, G. W., Miller, B., & Stevens, J. C. (2001) · Neurology · doi:10.1212/wnl.56.9.1143 · Cited by 1,410 · see citing works
Self-citationClinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial
Gilman, S., Koller, M., Black, R. S., Jenkins, L., Griffith, S. G., Fox, N. C., Eisner, L., Kirby, L., Rovira, M. B., Forette, F., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000159740.16984.3c · Cited by 1,329 · see citing works
CSF markers for incipient Alzheimer's disease
Blennow, K., & Hampel, H. (2003) · The Lancet Neurology · doi:10.1016/s1474-4422(03)00530-1 · Cited by 1,291 · see citing works
Improved discrimination of AD patients using β-amyloid <sub>(1-42)</sub> 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 · see citing works
Visser, P. J., Verhey, F., Knol, D. L., Scheltens, P., Wahlund, L.-O., Freund-Levi, Y., Tsolaki, M., Minthon, L., Wallin, Å. K., Hampel, H., et al. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70139-5 · Cited by 614 · see citing works
Ovod, V., Ramsey, K. N., Mawuenyega, K. G., Bollinger, J. G., Hicks, T., Schneider, T., Sullivan, M., Paumier, K., Holtzman, D. M., Morris, J. C., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.06.2266 · Cited by 585 · see citing works
Plasma and Cerebrospinal Fluid Levels of Amyloid β Proteins 1-40 and 1-42 in Alzheimer Disease
Mehta, P. D., Pirttilä, T., Mehta, S. P., Sersen, E. A., Aisen, P. S., & Wisniewski, H. M. (2000) · Archives of Neurology · doi:10.1001/archneur.57.1.100 · Cited by 582 · see citing works
Evaluation of CSF-tau and CSF-Aβ42 as diagnostic markers for Alzheimer disease in clinical practice
Andreasen, N., Minthon, L., Davidsson, P., Vanmechelen, E., Vanderstichele, H., Winblad, B., & Blennow, K. (2001) · Archives of Neurology · doi:10.1001/archneur.58.3.373 · Cited by 573 · see citing works
Linking Aβ and Tau in Late-Onset Alzheimer's Disease: A Dual Pathway Hypothesis
Small, S. A., & Duff, K. (2008) · Neuron · doi:10.1016/j.neuron.2008.11.007 · Cited by 546 · see citing works
Intrathecal inflammation precedes development of Alzheimer's disease
Tarkowski, E. (2003) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.74.9.1200 · Cited by 501 · see citing works
Hampel, H., Buerger, K., Zinkowski, R., Teipel, S. J., Goernitz, A., Andreasen, N., Sjoegren, M., DeBernardis, J., Kerkman, D., Ishiguro, K., et al. (2004) · Archives of General Psychiatry · doi:10.1001/archpsyc.61.1.95 · Cited by 434 · see citing works
Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide
Hu, X., Crick, S. L., Bu, G., Frieden, C., Pappu, R. V., & Lee, J.-M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911281106 · Cited by 426 · see citing works
Fagan, A. M., Head, D., Shah, A. R., Marcus, D., Mintun, M., Morris, J. C., & Holtzman, D. M. (2009) · Annals of Neurology · doi:10.1002/ana.21559 · Cited by 327 · see citing works
Standardization of measurement of β-amyloid<sub>(1-42)</sub>in cerebrospinal fluid and plasma
Vanderstichele, H., Kerschaver, E. V., Hesse, C., Davidsson, P., Buyse, M.-A., Andreasen, N., Minthon, L., Wallin, A., Blennow, K., & Vanmechelen, E. (2000) · Amyloid · doi:10.3109/13506120009146438 · Cited by 301 · see citing works
Hampel, H., Teipel, S. J., Fuchsberger, T., Andreasen, N., Wiltfang, J., Otto, M., Shen, Y., Dodel, R., Du, Y., Farlow, M., et al. (2004) · Molecular Psychiatry · doi:10.1038/sj.mp.4001473 · Cited by 287 · see citing works
A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease
Salloway, S., Sperling, R., Keren, R., Porsteinsson, A. P., van Dyck, C. H., Tariot, P. N., Gilman, S., Arnold, D., Abushakra, S., Hernandez, C., et al. (2011) · Neurology · doi:10.1212/wnl.0b013e3182309fa5 · Cited by 258 · see citing works
Bates, K. A., Verdile, G., Li, Q.-X., Ames, D., Hudson, P., Masters, C. L., & Martins, R. N. (2009) · Molecular Psychiatry · doi:10.1038/mp.2008.96 · Cited by 247 · see citing works
Fluid Biomarkers in Alzheimer Disease
Blennow, K., Zetterberg, H., & Fagan, A. M. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006221 · Cited by 208 · see citing works
Maddalena, A., Papassotiropoulos, A., Müller-Tillmanns, B., Jung, H. H., Hegi, T., Nitsch, R. M., & Hock, C. (2003) · Archives of Neurology · doi:10.1001/archneur.60.9.1202 · Cited by 204 · see citing works
Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease
Vemuri, P., Wiste, H. J., Weigand, S. D., Knopman, D. S., Shaw, L. M., Trojanowski, J. Q., Aisen, P. S., Weiner, M., Petersen, R. C., Jack, C. R., et al. (2010) · Annals of Neurology · doi:10.1002/ana.21953 · Cited by 195 · see citing works
Self-citationCSF biomarkers for mild cognitive impairment
Blennow, K. (2004) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2004.01368.x · Cited by 151 · see citing works
Herukka, S.-K., Simonsen, A. H., Andreasen, N., Baldeiras, I., Bjerke, M., Blennow, K., Engelborghs, S., Frisoni, G. B., Gabryelewicz, T., Galluzzi, S., et al. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.09.009 · Cited by 141 · see citing works
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 · see citing works
Self-citation<i>APOE</i> ε4 allele is associated with reduced cerebrospinal fluid levels of Aβ42
Prince, J. A., Zetterberg, H., Andreasen, N., Marcusson, J., & Blennow, K. (2004) · Neurology · doi:10.1212/01.wnl.0000128088.08695.05 · Cited by 128 · see citing works
Ewers, M., Zhong, Z., Bürger, K., Wallin, A., Blennow, K., Teipel, S. J., Shen, Y., & Hampel, H. (2008) · Brain · doi:10.1093/brain/awn034 · Cited by 119 · see citing works
Mild cognitive impairment in symptomatic and asymptomatic cerebrovascular disease
Popović, I. M., Šerić, V., & Demarin, V. (2007) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2007.01.029 · Cited by 113 · see citing works
Boada, M., Anaya, F., Ortiz, P., Olazarán, J., Shua-Haim, J. R., Obisesan, T. O., Hernández, I., Muñoz, J., Buendia, M., Alegret, M., et al. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-160565 · Cited by 94 · see citing works
Bendlin, B. B., Carlsson, C. M., Johnson, S. C., Zetterberg, H., Blennow, K., Willette, A. A., Okonkwo, O. C., Sodhi, A., Ries, M. L., Birdsill, A. C., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037720 · Cited by 91 · see citing works
Wattmo, C., Blennow, K., & Hansson, O. (2020) · BMC Neurology · doi:10.1186/s12883-019-1591-0 · Cited by 93 · see citing works
Kauwe, J. S. K., Jacquart, S., Chakraverty, S., Wang, J., Mayo, K., Fagan, A. M., Holtzman, D. M., Morris, J. C., & Goate, A. M. (2007) · Annals of Neurology · doi:10.1002/ana.21099 · Cited by 84 · see citing works
Stefani, A., Sancesario, G., Pierantozzi, M., Leone, G., Galati, S., Hainsworth, A. H., & Diomedi, M. (2009) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2009.02.343 · Cited by 80 · see citing works
Meng, Y., Baldwin, C. T., Bowirrat, A., Waraska, K., Inzelberg, R., Friedland, R. P., & Farrer, L. A. (2006) · The American Journal of Human Genetics · doi:10.1086/503687 · Cited by 72 · see citing works
Ocular manifestations of Alzheimer's disease in animal models
Parnell, M., Guo, L., Abdi, M., & Cordeiro, M. F. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/786494 · Cited by 56 · see citing works
The levels of cerebrospinal fluid Aβ40 and Aβ42(43) are regulated age-dependently
Shoji, M., Kanai, M., Matsubara, E., Tomidokoro, Y., Shizuka, M., Ikeda, Y., Ikeda, M., Harigaya, Y., Okamoto, K., & Hirai, S. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00229-3 · Cited by 50 · see citing works
Magnetic resonance and PET studies in the early diagnosis of Alzheimer’s disease
Mosconi, L., De Santi, S., Rusinek, H., Convit, A., & de Leon, M. J. (2004) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.4.5.831 · Cited by 46 · see citing works
Llano, D. A., Devanarayan, P., & Devanarayan, V. (2019) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000328 · Cited by 35 · see citing works
- Authors
- Galasko, D., Chang, L., Motter, R., Clark, C. M., Kaye, J., Knopman, D., Thomas, R., Kholodenko, D., Schenk, D., Lieberburg, I., Miller, B., Green, R., Basherad, R., Kertiles, L., Boss, M. A., & Seubert, P.
- Affiliations
- University of California San Diego (US)
- University of California, Los Angeles (US)
- Elan Pharmaceuticals, Inc. (Ireland) (IE)
- University of Pennsylvania (US)
- Oregon Health & Science University (US)
- Fairview Health Services (US)
- Georgia State University (US)
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 1998-07-01
- Volume
- 55
- Issue
- 7
- Pages
- 937
- ISSN
- 0003-9942 (ISSN-L)
- OpenAlex
- W2134379460
- Cited by
- 442
- References
- 1
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 9 · 2021: 6 · 2020: 7 · 2019: 9 · 2018: 13 · 2017: 12 · 2016: 15 · 2015: 10 · 2014: 17 · 2013: 10 · 2012: 17
- FWCI
- 15.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mashhad University of Medical Sciences
- 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, cerebrospinal fluid biomarkers, amyloid-beta 42, tau protein, APOE ε4, APOE genotype, mild dementia, early diagnosis, classification trees, diagnostic accuracy, differential diagnosis of dementia, sex differences, autopsy confirmation
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Dementia, Diagnosis, Differential, Female, Genotype, Humans, Male, Middle Aged, Neuropeptides, Peptide Fragments, Biomarkers, Amyloid beta-Peptides, tau Proteins
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
