Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Mar 22;3(3):CD010803.
doi: 10.1002/14651858.CD010803.pub2.

CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)

Craig Ritchie  1 , Nadja Smailagic  2 , Anna H Noel-Storr  3 , Obioha Ukoumunne  4 , Emma C Ladds  5 , Steven Martin  2
Affiliations

CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)

Craig Ritchie et al. Cochrane Database Syst Rev. .

Abstract

Background: Research suggests that measurable change in cerebrospinal fluid (CSF) biomarkers occurs years in advance of the onset of clinical symptoms (Beckett 2010). In this review, we aimed to assess the ability of CSF tau biomarkers (t-tau and p-tau) and the CSF tau (t-tau or p-tau)/ABeta ratio to enable the detection of Alzheimer's disease pathology in patients with mild cognitive impairment (MCI). These biomarkers have been proposed as important in new criteria for Alzheimer's disease dementia that incorporate biomarker abnormalities.

Objectives: To determine the diagnostic accuracy of 1) CSF t-tau, 2) CSF p-tau, 3) the CSF t-tau/ABeta ratio and 4) the CSF p-tau/ABeta ratio index tests for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease dementia or other forms of dementia at follow-up.

Search methods: The most recent search for this review was performed in January 2013. We searched MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (Thomson Reuters Web of Science), Web of Science Core Collection, including Conference Proceedings Citation Index (Thomson Reuters Web of Science), PsycINFO (OvidSP), and LILACS (BIREME). We searched specialized sources of diagnostic test accuracy studies and reviews. We checked reference lists of relevant studies and reviews for additional studies. We contacted researchers for possible relevant but unpublished data. We did not apply any language or data restriction to the electronic searches. We did not use any methodological filters as a method to restrict the search overall.

Selection criteria: We selected those studies that had prospectively well-defined cohorts with any accepted definition of MCI and with CSF t-tau or p-tau and CSF tau (t-tau or p-tau)/ABeta ratio values, documented at or around the time the MCI diagnosis was made. We also included studies which looked at data from those cohorts retrospectively, and which contained sufficient data to construct two by two tables expressing those biomarker results by disease status. Moreover, studies were only selected if they applied a reference standard for Alzheimer's disease dementia diagnosis, for example, the NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria.

Data collection and analysis: We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies, and the full papers for eligibility. Two independent assessors performed data extraction and quality assessment. Where data allowed, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic (ROC) curve.

Main results: In total, 1282 participants with MCI at baseline were identified in the 15 included studies of which 1172 had analysable data; 430 participants converted to Alzheimer's disease dementia and 130 participants to other forms of dementia. Follow-up ranged from less than one year to over four years for some participants, but in the majority of studies was in the range one to three years. Conversion to Alzheimer's disease dementia The accuracy of the CSF t-tau was evaluated in seven studies (291 cases and 418 non-cases).The sensitivity values ranged from 51% to 90% while the specificity values ranged from 48% to 88%. At the median specificity of 72%, the estimated sensitivity was 75% (95% CI 67 to 85), the positive likelihood ratio was 2.72 (95% CI 2.43 to 3.04), and the negative likelihood ratio was 0.32 (95% CI 0.22 to 0.47).Six studies (164 cases and 328 non-cases) evaluated the accuracy of the CSF p-tau. The sensitivities were between 40% and 100% while the specificities were between 22% and 86%. At the median specificity of 47.5%, the estimated sensitivity was 81% (95% CI: 64 to 91), the positive likelihood ratio was 1.55 (CI 1.31 to 1.84), and the negative likelihood ratio was 0.39 (CI: 0.19 to 0.82).Five studies (140 cases and 293 non-cases) evaluated the accuracy of the CSF p-tau/ABeta ratio. The sensitivities were between 80% and 96% while the specificities were between 33% and 95%. We did not conduct a meta-analysis because the studies were few and small. Only one study reported the accuracy of CSF t-tau/ABeta ratio.Our findings are based on studies with poor reporting. A significant number of studies had unclear risk of bias for the reference standard, participant selection and flow and timing domains. According to the assessment of index test domain, eight of 15 studies were of poor methodological quality.The accuracy of these CSF biomarkers for 'other dementias' had not been investigated in the included primary studies. Investigation of heterogeneity The main sources of heterogeneity were thought likely to be reference standards used for the target disorders, sources of recruitment, participant sampling, index test methodology and aspects of study quality (particularly, inadequate blinding).We were not able to formally assess the effect of each potential source of heterogeneity as planned, due to the small number of studies available to be included.

Authors' conclusions: The insufficiency and heterogeneity of research to date primarily leads to a state of uncertainty regarding the value of CSF testing of t-tau, p-tau or p-tau/ABeta ratio for the diagnosis of Alzheimer's disease in current clinical practice. Particular attention should be paid to the risk of misdiagnosis and overdiagnosis of dementia (and therefore over-treatment) in clinical practice. These tests, like other biomarker tests which have been subject to Cochrane DTA reviews, appear to have better sensitivity than specificity and therefore might have greater utility in ruling out Alzheimer's disease as the aetiology to the individual's evident cognitive impairment, as opposed to ruling it in. The heterogeneity observed in the few studies awaiting classification suggests our initial summary will remain valid. However, these tests may have limited clinical value until uncertainties have been addressed. Future studies with more uniformed approaches to thresholds, analysis and study conduct may provide a more homogenous estimate than the one that has been available from the included studies we have identified.

PubMed Disclaimer

Conflict of interest statement

Craig Ritchie ‐ None known Nadja Smailagic ‐ None known Anna H Noel‐Storr ‐ None known Obioha Ukoumunne ‐ None known Emma C Ladds ‐ None known Steven Martin ‐ None known

Figures

1
1
Study flow diagram Note: a top‐up search performed in December 2015 revealed 6134 records 85 records retained after de‐duplication and assessment by one experienced reviewer 81 records excluded after further assessment performed by two review authors 4 studies identified for possible inclusion (Characteristics of studies awaiting classification)
2
2
Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study
3
3
Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies
4
4
Forest plot of 1 CSF t‐tau conversion to AD dementia.
5
5
Summary ROC Plot of 1 CSF t‐tau conversion to AD dementia.
6
6
Post‐test probability plots (Analysis 1): Conversion from MCI to Alzheimer’s disease for CSF t‐tau as a diagnostic test
7
7
Forest plot of 2 CSF p‐tau conversion to AD dementia.
8
8
Summary ROC Plot of 2 CSF p‐tau conversion to AD dementia.
9
9
Post‐test probability plots (Analysis 2): Conversion from MCI to Alzheimer’s disease for CSF p‐tau as a diagnostic test
10
10
Forest plot of 3 CSF p‐tau/ABeta ratio to AD dementia.
11
11
Summary ROC Plot of 3 CSF p‐tau/ABeta ratio to AD dementia.
12
12
Forest plot of 4 CSF t‐tau conversion to all forms of dementia.
13
13
Summary ROC Plot of 4 CSF t‐tau conversion to All dementias.
1
1. Test
CSF t‐tau conversion to AD dementia.
2
2. Test
CSF p‐tau conversion to AD dementia.
3
3. Test
CSF p‐tau/ABeta ratio to AD dementia.
4
4. Test
CSF t‐tau conversion to All dementias.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD010803

References

References to studies included in this review

Amlien 2013 {published and unpublished data}
    1. Amlien IK, Fjeli AM, Walhovd KB, Selnes P, Stenset V, Grambaite R, at al. Mild cognitive impairment: cerebrospinal fluid tau biomarker pathologic levels and longitudinal changes in white matter integrity. Radiology 2013;266:295‐303. - PubMed
Buchhave 2012 {published data only}
    1. Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O. Cerebrospinal fluid levels of beta‐amyloid 1‐42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Archives of General Psychiatry 2012;69(1):98‐106. - PubMed
    1. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302(4):385‐93. - PubMed
Eckerstrom 2010 {published data only}
    1. Eckerström C, Andreasson U, Olsson E, Rolstad S, Blennow K, Zetterberg H, et al. Combination of hippocampal volume and cerebrospinal fluid biomarkers Improves predictive value in mild cognitive impairment. Dementia and Geriatric Cognitive Disorders 2010;29:294‐300. - PubMed
    1. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302(4):385‐93. - PubMed
    1. Wallin A, Göthlin M, Gustavsson M, Zetterberg H. Eckerström C, Blennow K, et al. Progression from mild to pronounced MCI Is not associated with cerebrospinal fluid biomarker deviations. Dementia and Geriatric Cognitive Disorders 2011;32:193‐7. - PubMed
Fellgiebel 2007 {published data only}
    1. Fellgiebel A, Scheurich A, Bartenstein P, Müller MJ. FDG‐PET and CSF phospho‐tau for prediction of cognitive decline in mild cognitive impairment. Psychiatry Research: Neuroimaging 2007;155:167‐71. - PubMed
Galluzzi 2010 {published and unpublished data}
    1. Galluzzi S, Geroldi C, Ghidoni R, Paghera B, Amicucci G, Bonetti M, et al. The new Alzheimer's criteria in a naturalistic series of patients with mild cognitive impairment. Journal of Neurology 2010;257(12):2004‐14. - PubMed
Hampel 2004 {published data only}
    1. Hampel H, Teipel SJ, Fuchsberger T, Andreasen N, Wiltfang J, Otto M, at al. Value of CSF ß‐amyloid1‐42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment. Molecular Psychiatry 2004;9:705‐10. - PubMed
Hansson 2006 {published and unpublished data}
    1. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow‐up study. Lancet Neurology 2006;5:228‐34. - PubMed
    1. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302(4):385‐93. - PubMed
Herukka 2007 {published data only}
    1. Herukka SK, Hallikainen M, Soininen H, Pirttila T. CSF Ab42 and tau or phosphorylated tau and prediction of progressive mild cognitive impairment. Neurology 2005;64:1294‐7. - PubMed
    1. Herukka SK, Hallikainen M, Tervo S, Helisalmi S, Tapiola T, Soininen T, et al. Cerebrospinal fluid Aβ42, tau and phosphorylated tau predict progression in patients with cognitive impairment. Research and Practice in Alzheimer's disease 2006;11:245‐50.
    1. Herukka SK, Helisalmi S, Hallikainen M, Tervo S, Soininen H, Pirttila T. CSF Aß42, tau and phosphorylated tau, APOE ϵ4 allele and MCI type in progressive MCI. Neurobiology of Aging 2007;28:507‐14. - PubMed
    1. Herukka SK, Pennanen C, Soininen H, Pirttila T. CSF Aβ42, tau and phosphorylated tau correlate with medial temporal lobe atrophy. Journal of Alzheimer's Disease 2008;14:51‐7. - PubMed
    1. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302(4):385‐93. - PubMed
Kester 2011 {published data only}
    1. Kester MI, Verwey NA, Elk EJ, Blankenstein MA, Scheltens P, Flier WM. Progression from MCI to AD: predictive value of CSF Aβ42 is modified by APOE genotype. Neurobiology of Aging 2011;32(8):1372‐8. - PubMed
    1. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302(4):385‐93. - PubMed
Koivunen 2008 {published data only}
    1. Koivunen J, Pirttilä T, Kemppainen N, Aalto S, Herukka S‐K, Jauhianen AM, et al. PET amyloid ligand [11C]PIB uptake and cerebrospinal fluid β‐amyloid in mild cognitive Impairment. Dementia and Geriatric Cognitive Disorders 2008;26:378‐83. - PubMed
Monge‐Argiles 2011 {published data only}
    1. Monge‐Argiles JA, Munoz‐Ruiz C, Pampliega‐Perez A, Gomez‐Lopez MJ, Sanchez‐Paya J, Rodriguez‐Borja E, et al. Biomarkers of Alzheimer's disease in the cerebrospinal fluid of Spanish patients with mild cognitive impairment. Neurochemical Research 2011;36:986‐93. - PubMed
    1. Monge‐Argiles JA, Sanchez‐Payab J, Munoz‐Ruiz C, Pampliega‐Perez A, Gomez‐Lopez MJ, Borja ER, et al. Patients with mild cognitive impairment and a reduced CSF Aβ1‐42 protein progress rapidly to Alzheimer’s disease. Neurologia 2012;27(1):28‐33. - PubMed
Palmqvist 2012 {published data only}
    1. Hertzel J, Minthono L, Zetterberg H, Vanmechelend E, Blcnnowc K, Hanssonllb O. Evaluation of CSF biomarkers as predictors of Alzheimer's disease: a clinical follow‐up study of 4.7 years. Journal of Alzheimer's Disease 2010;21:1119‐28. - PubMed
    1. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302(4):385‐93. - PubMed
    1. Palmqvist S, Hertze J, Minthon L, Wattmo C, Zetterberg Z, Blennow K, at al. Comparison of brief cognitive tests and CSF biomarkers in predicting Alzheimer’s disease in mild cognitive impairment: six‐year follow‐up study. PLoS ONE 2012;7(6):e38639. [DOI: 10.1371/journal.pone.0038639] - DOI - PMC - PubMed
Parnetti 2012 {published data only}
    1. Parnetti L, Chiasserini D, Eusebi P, Giannandrea D, Bellomo G, Carlo C, et al. Performance of Aβ1‐40, Aβ1‐42, total tau,and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment. Journal of Alzheimer's Disease 2012;29:229‐38. - PubMed
Visser 2009 {published and unpublished data}
    1. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302(4):385‐93. - PubMed
    1. Visser PJ, Verhey F, Knol DL, Scheltens P, Wahlund L‐O, Freund‐Levi Y, et al. Prevalence and prognostic value of CSF markers of Alzheimer’s disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurology 2009;8:619‐27. - PubMed
Vos 2013 {published and unpublished data}
    1. Vos SJB, Rossum IA, Verhey F, Knol DL, Soininen H, Wahlund L‐O, et al. Prediction of Alzheimer disease in subjects with amnestic and nonamnestic MCI. Neurology 2013;80:1‐9. - PubMed

References to studies excluded from this review

Desikan 2011 {published data only}
    1. Desikan RS, McEvoy LK, Thompson WK, Holland D, Roddey JC, Blennow K, et al. Amyloid‐β associated volume loss occurs only in the presence of phospho‐tau. Annals of Neurology 2011;70:657‐61. - PMC - PubMed
Forlenza 2010 {published data only}
    1. Forlenza OV, Diniz BS, Talib LL, Radanovic M, Yassuda MS, Ojopi EB, et al. Clinical and biological predictors of Alzheimer’s disease inpatients with amnestic mild cognitive impairment. Revista Brasileira de Psiquiatria 2010;32(3):216‐22. - PubMed
Holland 2012 {published data only}
    1. Holland D, Desikan RS, Dale AM, McEvoy LK, Alzheimer’s Disease Neuroimaging Initiative. Rates of decline in Alzheimer Disease decrease with age. PLOS One 2012;7(8):e42325. [DOI: 10.1371/journal.pone.0042325] - DOI - PMC - PubMed
Ivanoiu 2005 {published data only}
    1. Ivanoiu A, Sindic CJ. Cerebrospinal fluid tau protein and amyloid β42 in mild cognitive impairment: prediction of progression to Alzheimer’s disease and correlation with the neuropsychological examination. Neurocase 2005;11(1):32‐9. - PubMed
Jack 2011 {published data only}
    1. Jack CR, Vemuri P, Wiste BA, Weigand SD, Aisen PS, Trojanowski J, et al. Evidence for ordering of Alzheimer disease biomarkers. Archives of Neurology 2011;68(12):1526‐35. - PMC - PubMed
Jagust 2009 {published data only}
    1. Jagust WJ, Landau SM, Shaw M, Trojanowski JQ, Koeppe RA, Reiman EM, et al. Relationships between biomarkers in aging and dementia. American Academy of Neurology 2009;73:1193‐9. - PMC - PubMed
Lanari 2009 {published data only}
    1. Lanari A, Parnetti L. Cerebrospinal fluid biomarkers and prediction of conversion in patients with mild cognitive Impairment: 4‐year follow‐up in a routine clinical setting. Scientific World 2009;9:961‐6. - PMC - PubMed
Landau 2010 {published data only}
    1. Davatzikosa C, Bhatta P, Shawb LM, Batmanghelich KN, Trojanowski JQ. Prediction of MCI to AD conversion, via MRI, CSF biomarkers, and pattern classification. Neurobiology of Aging 2011;32:2322.e19‐2322.e27. - PMC - PubMed
    1. Ewers M, Schmitz S, Hansson O, Walsh C, Fitzpatrick A, Bennett D, et al. Body mass index is associated with biological CSF markers of core brain pathology of Alzheimer’s disease. Neurobiology of Aging 2012;33:1599‐608. - PMC - PubMed
    1. Ewers M, Walsh C, Trojanowski JQ, Shaw LM, Petersen RC, Jack Jr. CR, et al. Prediction of conversion from mild cognitive impairment to Alzheimer’s disease dementia based upon biomarkers and neuropsychological test performance. Neurobiology of Aging 2012;33:1203‐14. - PMC - PubMed
    1. Gomar JJ, Bobes‐Bascaran MT, Conejero‐Goldberg C, Davies P, Goldberg TE. Utility of combinations of biomarkers, cognitive markers, and risk factors to predict conversion from mild cognitive impairment to Alzheimer disease in patients in the Alzheimer’s Disease Neuroimaging Initiative. Archives of General Psychiatry 2011;68(9):961‐9. - PubMed
    1. Landau SM, Harvey D, Madison CM, Reiman EM, Foster NL, Aisen PS, et al. Comparing predictors of conversion and decline in mild cognitive impairment. Neurology 2010;75:230‐8. - PMC - PubMed
Maruyama 2004 {published data only}
    1. Maruyama M, Matsui T, Tanji H, Nemoto M, Tomita N, Ootsuki M, et al. Cerebrospinal fluid tau protein and periventricular white matter lesions in patients with mild cognitive impairment. Archives of Neurology 2004;61:716‐20. - PubMed
Maruyama 2004b {published data only}
    1. Maruyama M, Matsui T, Tanji H, Ootsuki M, Nemoto M, Tomita N, et al. Diagnosing the mild cognitive impairment stage of Alzheimer's disease. Psychiatria et Neurologia Japonica 2004;106(3):269‐80. - PubMed
Mattsson 2012 {published data only}
    1. Mattsson N, Porteliusa E, Rolstad S, Gustavsson M, Andreasson U, Stridsberg M, et al. Longitudinal cerebrospinal fluid biomarkers over four years in mild cognitive impairment. Journal of Alzheimer's Disease 2012;30:767‐78. - PubMed
Nordlund 2010 {published data only}
    1. Nordlund A, Rolstad S, Klang O, Edman A, Hansen S, Wallin A. Two‐year outcome of MCI subtypes and aetiologies in the Goteborg MCI study. Journal of Neurology, Neurosurgery, and Psychiatry 2010;81:541‐6. - PubMed
Okamura 2002 {published data only}
    1. Okamura N, Arai H, Maruyama M, Higuchi M, Matsui T, Tanji H, et al. Combined analysis of CSF tau levels and [123I]Iodoamphetamine SPECT in mild cognitive impairment: implications for a novel predictor of Alzheimer’s Disease. American Journal of Psychiatry 2002;159:474–6. - PubMed
Okonkwo 2011 {published data only}
    1. Okonkwo OC, Mielke MM, Griffith HR, Moghekar AR, O’Brien RJ, Shaw LM, et al. Cerebrospinal fluid profiles and prospective course and outcome in patients with amnestic mild cognitive impairment. Archives of Neurology 2011;68(1):113‐9. - PMC - PubMed
Pereira 2010 {published data only}
    1. Pereira FS, Yassuda MS, Olivira AM, Diniz BS, Radanovic M, Talib LL, et al. Profiles of functional deficits in mild cognitive impairment and dementia: benefits from objective measurement. International Neuropsychological Society 2010;16:297‐305. - PubMed
Perneczky 2011 {published data only}
    1. Perneczky R, Tsolakidou A, Arnold A, Diehl‐Schmid J, Grimmer T, Forstl H, et al. CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease. Neurology 2011;77:35‐8. - PubMed
Riemenschneider 2002 {published data only}
    1. Riemenschneider M, Lautenschlager N, Wagenpfeil S, Diehl J, Drzezga A, Kurz A. Cerebrospinal fluid tau and beta‐amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment. Archives of Neurology 2002;59(11):1729‐34. - PubMed
Samtani 2012 {published data only}
    1. Samtani MN, Raghavan N, Shi Y, Novak G, Farnum M, Lobanov V, et al. Disease progression model in subjects with mild cognitive impairment from the Alzheimer’s disease neuroimaging initiative: CSF biomarkers predict population subtypes. British Journal of Clinical Pharmacology 2012;75(1):146‐61. - PMC - PubMed
Schneider 2010 {published data only}
    1. Schneider LS, Kennedy RE, Cutter GR, Alzheimer’s Disease Neuroimaging Initiative. Requiring an amyloid‐b1‐42 biomarker for prodromal Alzheimer’s disease or mild cognitive impairment does not lead to more efficient clinical trials. Alzheimers & Dementia 2010;6:e367‐77. - PMC - PubMed
Shaw 2009 {published data only}
    1. Shaw LM, Vanderstichele H, Knapik‐Czajka M, Clark CM, Aisen PS, Petersen RC, et al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Annals of Neurology 2009;65:403‐13. - PMC - PubMed
Sluimer 2010 {published data only}
    1. Sluimer JD, Bouwman FH, Vrenken H, Blankenstein MA, Barkhof F, Flier WM, et al. Whole‐brain atrophy rate and CSF biomarker levels in MCI and AD: a longitudinal study. Neurobiology of Aging 2010;31:758‐64. - PubMed
Snider 2009 {published data only}
    1. Snider BJ, Fagan AM, Roe C, Shah AR, Grant EA, Xiong C. Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type. Archives of Neurology 2009;66(5):638‐45. - PMC - PubMed
Van Harten 2012 {published data only}
    1. Harten AC, Visser PJ, Pijnenburg YAL, Teunissen CE, Blankenstein MA, Scheltens P, et al. Cerebrospinal fluid Aß42 is the best predictor of clinical progression in patients with subjective complaints. Alzheimers & Dementia 2013;9:481‐7. - PubMed
Verwey 2008 {published data only}
    1. Verwey NA, Bouwman FH, Flier WM, Veerhuis R, Scheltens P, Blankenstein MA. Variability in longitudinal cerebrospinal fluid tau and phosphorylated tau measurements. Clinical Chemistry and Laboratory Medicine 2008;46(9):1300‐4. - PubMed
Walhovd 2010 {published data only}
    1. Walhovd KB, Fjell AM, Brewer J, McEvoy LK, Fennema‐Notestine C, Hagler DJ Jr, et al. Combining MR imaging, positron‐emissiontomography, and CSF biomarkers in the diagnosis and prognosis of Alzheimer disease. American Journal of Neuroradiology 2010;31(2):347‐54. - PMC - PubMed
Wang 2012 {published data only}
    1. Wang L, Fagan AM, Shah AR, Beg MF, Csernansky JG, Morris JC, et al. Cerebrospinal fluid proteins predict longitudinal hippocampal degeneration in early‐stage dementia of the Alzheimer type. Alzheimer Disease and Associated Disorders 2012;26:314‐21. - PMC - PubMed
Westman 2012 {published data only}
    1. Westman E, Muehlboeck J‐S, Simmons A. Combining MRI and CSF measures for classification of Alzheimer's disease and prediction of mild cognitive impairment conversion. Neurolmage 2012;62:229‐38. - PubMed
Yang 2012 {published data only}
    1. Yang X, Tan MZ, Qiu A. CSF and brain structural imaging markers of the Alzheimer’s pathological cascade. PLOS One 2012;7(12):e47406. - PMC - PubMed

References to studies awaiting assessment

Balasa 2014 {published data only}
    1. Balasa M, Sanchez‐Valle R, Antonell A, Bosch B, Olives J, Rami L, et al. Usefulness of biomarkers in the diagnosis and prognosis of early‐onset cognitive impairment. Journal of Alzheimer's Disease 2014;40(4):919‐27. - PubMed
Eckerstrom 2015 {published data only}
    1. Eckerström C, Olsson E, Klasson N, Berge J, Nordlund A, Bjerke M, et al. Multimodal prediction of dementia with up to 10 years follow up: the Gothenburg MCI study. Journal of Alzheimer's disease 2015;44(1):205‐14. - PubMed
Ewers 2012 {published data only}
    1. Ewers M, Walsh C, Trojanowski JQ, Shaw LM, Petersen RC, Jack CR Jr, et al. North American Alzheimer's Disease Neuroimaging Initiative (ADNI). Prediction of conversion from mild cognitive impairment to Alzheimer's disease dementia based upon biomarkers and neuropsychological test performance. Neurobiology of Aging 2012;33(7):1203‐14. - PMC - PubMed
Leuzy 2015 {published data only}
    1. Leuzy A, Carter SF, Chiotis K, Almkvist O, Wall A, Nordberg A. Concordance and diagnostic accuracy of [11C]PIB PET and cerebrospinal fluid biomarkers in a sample of patients with mild cognitive impairment and Alzheimer's disease. Journal of Alzheimer's Disease 2015;45(4):1077‐88. - PubMed

Additional references

Albert 2011
    1. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendation from the National Institute on Ageing and Alzheimer’s Association workgroup. Alzheimers & Dementia 2011;7(3):270‐9. - PMC - PubMed
Arevalo‐Rodriguez 2015
    1. Arevalo‐Rodriguez I, Smailagic N, Roqué i Figuls M, Ciapponi A, Sanchez‐Perez E, Giannakou A, et al. Mini‐Mental State Examination (MMSE) for the detection of Alzheimer's disease and other dementias in people with mild cognitive impairment (MCI). Cochrane Database of Systematic Reviews 2015, Issue 3. [DOI: 10.1002/14651858.CD010783.pub2] - DOI - PMC - PubMed
Beckett 2010
    1. Beckett LA, Harvey DJ, Gamst A, Donohueb M, Kornak J, Zhang H, et al. The Alzheimer’s Disease Neuroimaging Initiative: annual change in biomarkers and clinical outcomes. Alzheimers & Dementia 2010;6:257‐64. - PMC - PubMed
Beynon 2013
    1. Beynon R, Leeflang MM, McDonald S, Eisinga A, Mitchell RL, Whiting P, et al. Search strategies to identify diagnostic accuracy studies in MEDLINE and EMBASE. Cochrane Database of Systematic Reviews 2013, Issue 9. [DOI: 10.1002/14651858.MR000022.pub3] - DOI - PMC - PubMed
Billingsley 1997
    1. Billingsley ML, Kincaid RL. Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochemical Journal 1997;323(3):577‐91. - PMC - PubMed
Blennow 2003
    1. Blennow K, Hampel H. CSF markers for incipient Alzheimer's disease. Lancet Neurology 2003; Vol. 2, issue 10:605‐13. - PubMed
Bossuyt 2008
    1. Bossuyt PM, Leeflang MM. Chapter 6: Developing criteria for including studies. Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy 2008:http://methods.cochrane.org/sdt/.
Bourne 2007
    1. Bourne J. Improving services and support for people with dementia. National Audit Office 2007.
Boxer 2005
    1. Boxer A, Miller B. Clinical features of frontotemporal dementia. Alzheimer Disease & Associated Disorders 2005;19:S3‐S6. - PubMed
Bruscoli 2004
    1. Bruscoli M, Lovestone S. Is MCI really just early dementia? A systematic review of conversion studies. International Psychogeriatrics 2004;16:129‐40. - PubMed
Davison 2003
    1. Davison AC. Statistical Models. Cambridge University Press, 2003.
DSMIII 1987
    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Association 1987. 3rd revised edition.
DSMIV 1994
    1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Washington, DC: American Psychiatric Association 1994. 4th edition.
Dubois 2007
    1. Dubois B, Feldman HH, Jacova C, DeKosky ST, Barberger‐Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria. Lancet Neurology 2007;6(8):734‐6. - PubMed
Dubois 2010
    1. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger‐Gateau P, et al. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurology 2010;9(11):1118‐27. - PubMed
Dubois 2014
    1. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo L, Blenonow K, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG‐2 criteria. Lancet Neurology 2014;13:614‐29. - PubMed
Ferri 2005
    1. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet 2005;366(9503):2112‐7. - PMC - PubMed
Geslani 2005
    1. Geslani D, Tierney M, Herrmann N, Szalai J. Mild cognitive impairment: an operational definition and its conversion rate to Alzheimer's disease. Dementia and Geriatric Cognitive Disorders 2005;19:383‐9. - PubMed
Knapp 2007
    1. Knapp M, Prince M. Dementia UK: A report to the Alzheimer's Society on the prevalence and economic cost of dementia in the UK produced by King's College London and London School of Economics. London (UK): Alzheimer's Society; 2007.
Knopman 2001
    1. Knopman D, DeKosky S, Cummings J, Chui H, Corey‐Bloom J, Relkin N, et al. Practice parameter: diagnosis of dementia (an evidence‐based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2001;56(9):1143‐53. - PubMed
Knottnerus 2002
    1. Knottnerus JA, Weel C, Muris JW. Evaluation of diagnostic procedures. BMJ 2002;324(7335):477‐80. - PMC - PubMed
LMG 1994
    1. Lund and Manchester Groups. Clinical and neuropathological criteria for frontotemporal dementia. Journal of Neurology, Neurosurgery, and Psychiatry 1994;57(4):416‐8. - PMC - PubMed
Mandelkow 1998
    1. Mandelkow EM, Mandelkow E. Tau in Alzheimer’s disease. Trends in Cell Biology 1998;8:4257. - PubMed
Mason 2010
    1. Mason SE, McShane R, Ritchie CW. Diagnostic tests for Alzheimer's disease: rationale, methodology, and challenges. International Journal of Alzheimer’s Disease 2010;2010:Article ID 972685. - PMC - PubMed
Matthews 2008
    1. Matthews FE, Stephan BC, McKeith IG, Bond J, Brayne C. Two‐year progression from mild cognitive impairment to dementia: to what extent do different definitions agree?. Journal of the American Geriatrics Society 2008;56(8):1424‐33. - PubMed
Matthews 2009
    1. Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P. Epidemiological pathology of dementia: attributable‐risks at death in the Medical Research Council Cognitive Function and Ageing study. PLOS Medicine 2009;6:e1000180. - PMC - PubMed
Mattsson 2009
    1. Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009;302(4):385‐93. - PubMed
McKeith 1996
    1. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; Vol. 47, issue 5:1113‐24. - PubMed
McKeith 2005
    1. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863‐72. - PubMed
McKhann 1984
    1. McKhann GM, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS‐ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 1984; Vol. 34, issue 7:939‐44. - PubMed
Molinuevo 2014
    1. Molinuevo JL, Blennow K, Dubois B, Engelborghs S, Lewczuk P, Perret‐Liaudet A, et al. The clinical use of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: a consensus paper from the Alzheimer's Biomarkers Standardisation Initiative. Alzheimers & Dementia 2014;10:808‐17. - PubMed
Morris 1993
    1. Morris JC. The clinical dementia rating (CDR): current version and scoring rules. Neurology 1993;43:2412‐4. - PubMed
MRC CFAS 2001
    1. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Pathological correlates of late‐onset dementia in a multicentre, community‐based population in England and Wales.. Lancet 2001;357(9251):169‐75. - PubMed
Neary 1998
    1. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546‐54. - PubMed
Noel‐Storr 2013
    1. Noel‐Storr AH, Flicker L, Ritchie CW, Nguyen GH, Gupta T, Wood P, et al. Systematic review of the body of evidence for use of biomarkers in the diagnosis of dementia. Alzheimers & Dementia 2013;9(3):e96‐e105. - PubMed
Noel‐Storr 2014
    1. Noel‐Storr AH, McCleeery JM, Richard E, Ritchie C, Flicker L, Cullum S, et al. Reporting standards for studies of diagnostic test accuracy in dementia. Neurology 2014;83:1‐10. - PMC - PubMed
Okello 2009
    1. Okello A, Koivunen J, Edison P, Archer HA, Turkheimer F, Nagren K, et al. Conversion of amyloid positive and negative MCI to AD over 3 years: an 11C‐PIB PET study. Neurology 2009;73(10):754‐60. - PMC - PubMed
Petersen 1999
    1. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Archives of Neurology 1999; Vol. 56:303‐8. - PubMed
Petersen 2004
    1. Petersen RC. Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine 2004;256(3):183‐94. - PubMed
Petersen 2009
    1. Petersen RC, Roberts RO, Knopman DS, Boeve BF, Geda YE, Ivnik RJ, et al. Mild cognitive impairment: ten years later. Archives of Neurology 2009;66(12):1447‐55. - PMC - PubMed
Petersen 2010
    1. Petersen R, Aisen PS, Beckett LA, Donohue MC, Gamst AC, Harvey DJ, et al. Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology 2010;74(3):201‐9. - PMC - PubMed
Prince 2013
    1. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. 2013; Vol. 9, issue 1:63‐75.e2. - PubMed
Quadas‐2
    1. University of Bristol. Quadas‐2. www.bris.ac.uk/quadas/quadas‐2 (accessed prior to 18 February 2017).
Quinn 2014
    1. Quinn TJ, Fearon P, Noel‐Storr AH, Young C, McShane R, Stott DJ. Informant Questionnaire on COgnitive Decline in the Elderly (IQCODE) for the diagnosis of dementia within community dwelling populations. Cochrane Database of Systematic Reviews 2014, Issue 4. [DOI: 10.1002/14651858.CD010079.pub2] - DOI - PubMed
Reisberg 1982
    1. Reisberg B, Ferris, SH, Leon MJ, Crook T. The global deterioration scale for assessment of primary degenerative dementia. American Journal of Psychiatry 1982;139(9):1136–9. - PubMed
Ritchie 2011
    1. Ritchie C, Masters CL, Mason SE, Li QX, McShane R. Plasma and CSF Abeta for the longitudinal prediction of Alzheimer's disease dementia and other dementias in people with cognitive decline but no dementia. Cochrane Database of Systematic Reviews 2011, Issue 1. [DOI: 10.1002/14651858.CD008782.pub3] - DOI
Ritchie 2014
    1. Ritchie C, Smailagic N, Noel‐Storr AH, Takwoingi Y, Flicker L, Mason SE, et al. Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database of Systematic Reviews 2014, Issue 6. [DOI: 10.1002/14651858.CD008782.pub4] - DOI - PMC - PubMed
Ritchie 2016
    1. Ritchie CW, Molinuevo JL, Truyen L, Saltin A, Geyten S, Lovestone S, European Prevention of Alzheimer's Dementia (EPAD) Consortium. Development of interventions for the secondary prevention of Alzheimer's dementia: the European Prevention of Alzheimer's Dementia (EPAD) project. Lancet Psychiatry 2016;3(2):179‐86.. [DOI: 10.1016/S2215-0366(15)00454-X] - DOI - PubMed
Roman 1993
    1. Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS‐AIREN international workshop. Neurology 1993; Vol. 43, issue 2:250‐60. - PubMed
SAS Institute 2011 [Computer program]
    1. SAS Institute. SAS Version 9.2. Cary, NC, USA, 2011.
Savva 2009
    1. Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C, et al. Age, neuropathology, and dementia. New England Journal of Medicine 2009;360(22):230‐9. - PubMed
Shoji 1992
    1. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, et al. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 1992;258(5079):126‐9. - PubMed
Shoji 2001
    1. Shoji M, Kanai M. Cerebrospinal fluid Ab40 and Ab42: natural course and clinical usefulness. Journal of Alzheimer's Disease 2001;3(3):313‐21. - PubMed
Shoji 2002
    1. Shoji M, Matsubara E, Murakami T, Manabe Y, Abe K, Kanai M, et al. Cerebrospinal fluid tau in dementia disorders: a large scale multicenter study by a Japanese study group. Neurobiology of Aging 2002; Vol. 23, issue 3:363‐70. - PubMed
Smailagic 2015
    1. Smailagic N, Vacante M, Hyde C, Martin S, Ukoumunne O, Sachpekidis C. 18F‐FDG PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database of Systematic Reviews 2015, Issue 1. [DOI: 10.1002/14651858.CD010632.pub2] - DOI - PMC - PubMed
Urakami 2004
    1. Urakami K, Saito K, Seishima M, Nakashima K. Apolipoprotein A‐I and E in cerebrospinal fluid. Nihon Rinsho. Japanese Journal of Clinical Medicine 2004;62 Suppl 11:176‐8. - PubMed
Visser 2006
    1. Visser PJ, Kester A, Jolles J, Verhey F. Ten‐year risk of dementia in subjects with mild cognitive impairment. Neurology 2006;67:1201‐07. - PubMed
Whiting 2011
    1. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al. QUADAS‐2: a revised tool for the quality assessment of diagnostic accuracy studies. Annals of Internal Medicine 2011;155:529‐36. - PubMed
Wilmo 2010
    1. Wilmo A, Prince M. World Alzheimer Report 2010: The global economic impact of dementia. www.alz.co.uk/research/files/WorldAlzheimerReport2010.pdf (accessed prior to 17 Feb 2017).
Winbald 2004
    1. Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, et al. Mild cognitive impairment ‐ beyond controversies, towards a consensus: report of the international working group on mild cognitive impairment. Journal of Internal Medicine 2004;256:240‐6. - PubMed
World Health Organization 2010
    1. World Health Organization. International statistical classification of diseases and related health problems (ICD‐10 Version: 2010). apps.who.int/classifications/icd10/browse/2010/en (accessed 9 January 2013):1‐195.
Zhang 2014
    1. Zhang S, Smailagic N, Hyde C, Noel‐Storr AH, Takwoingi Y, McShane R, at al. 11C‐PIB‐PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database of Systematic Reviews 2014, Issue 7. [DOI: 10.1002/14651858.CD010386] - DOI - PMC - PubMed

Publication types