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Meta-analysis of CSF and MRI biomarkers for detecting preclinical Alzheimer's disease

  • B. Schmand (a1) (a2), H. M. Huizenga (a2) and W. A. van Gool (a1)
  • DOI:
  • Published online: 29 October 2009

Abnormal levels of biomarkers in cerebrospinal fluid (CSF) and atrophy of medial temporal lobe (MTL) structures on magnetic resonance imaging (MRI) are being used increasingly to diagnose early Alzheimer's disease (AD). We evaluated the claim that these biomarkers can detect preclinical AD before behavioural (i.e. memory) symptoms arise.


We included all relevant longitudinal studies of CSF and MRI biomarkers published between January 2003 and November 2008. Subjects were not demented at baseline but some declined to mild cognitive impairment (MCI) or to AD during follow-up. Measures of tau and beta-amyloid in CSF, MTL atrophy on MRI, and performance on delayed memory tasks were extracted from the papers or obtained from the investigators.


Twenty-one MRI studies and 14 CSF studies were retrieved. The effect sizes of total tau (t-tau), phosphorylated tau (p-tau) and amyloid beta 42 (aβ42) ranged from 0.91 to 1.11. The effect size of MTL atrophy was 0.75. Memory performance had an effect size of 1.06. MTL atrophy and memory impairment tended to increase when assessed closer to the moment of diagnosis, whereas effect sizes of CSF biomarkers tended to increase when assessed longer before the diagnosis.


Memory impairment is a more accurate predictor of early AD than atrophy of MTL on MRI, whereas CSF abnormalities and memory impairment are about equally predictive. Consequently, the CSF and MRI biomarkers are not very sensitive to preclinical AD. CSF markers remain promising, but studies with long follow-up periods in elderly subjects who are normal at baseline are needed to evaluate this promise.

Corresponding author
*Address for correspondence: B. Schmand, Ph.D., Department of Neurology, H2-222, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands. (Email:
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This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

C Andersson , K Blennow , O Almkvist , N Andreasen , P Engfeldt , SE Johansson , M Lindau , M Eriksdotter-Jonhagen (2008). Increasing CSF phospho-tau levels during cognitive decline and progression to dementia. Neurobiology of Aging 29, 14661473.

L Bäckman , S Jones , AK Berger , EJ Laukka , BJ Small (2005). Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis. Neuropsychology 19, 520531.

AD Blackwell , BJ Sahakian , R Vesey , JM Semple , TW Robbins , JR Hodges (2004). Detecting dementia: novel neuropsychological markers of preclinical Alzheimer's disease. Dementia and Geriatric Cognitive Disorders 17, 4248.

K Blennow , H Hampel (2003). CSF markers for incipient Alzheimer's disease. Lancet Neurology 2, 605613.

PM Bossuyt , JB Reitsma , DE Bruns , CA Gatsonis , PP Glasziou , LM Irwig , JG Lijmer , D Moher , D Rennie , HC de Vet (2003). Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. British Medical Journal 326, 4144.

FH Bouwman , SN Schoonenboom , WM van der Flier , EJ van Elk , A Kok , F Barkhof , MA Blankenstein , P Scheltens (2007). CSF biomarkers and medial temporal lobe atrophy predict dementia in mild cognitive impairment. Neurobiology of Aging 28, 10701074.

M Brys , E Pirraglia , K Rich , S Rolstad , L Mosconi , R Switalski , L Glodzik-Sobanska , S De Santi , R Zinkowski , P Mehta , D Pratico , LA Saint Louis , A Wallin , K Blennow , MJ de Leon (2009). Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment. Neurobiology of Aging 30, 682690.

H Buschke , MJ Sliwinski , G Kuslansky , RB Lipton (1997). Diagnosis of early dementia by the Double Memory Test: encoding specificity improves diagnostic sensitivity and specificity. Neurology 48, 989997.

NE Carlson , MM Moore , A Dame , D Howieson , LC Silbert , JF Quinn , JA Kaye (2008). Trajectories of brain loss in aging and the development of cognitive impairment. Neurology 70, 828833.

OT Carmichael , LH Kuller , OL Lopez , PM Thompson , RA Dutton , A Lu , SE Lee , JY Lee , HJ Aizenstein , CC Meltzer , Y Liu , AW Toga , JT Becker (2007). Ventricular volume and dementia progression in the Cardiovascular Health Study. Neurobiology of Aging 28, 389397.

JG Csernansky , L Wang , J Swank , JP Miller , M Gado , D McKeel , MI Miller , JC Morris (2005). Preclinical detection of Alzheimer's disease: hippocampal shape and volume predict dementia onset in the elderly. NeuroImage 25, 783792.

C Davatzikos , Y Fan , X Wu , D Shen , SM Resnick (2008). Detection of prodromal Alzheimer's disease via pattern classification of magnetic resonance imaging. Neurobiology of Aging 29, 514523.

MJ de Leon , S DeSanti , R Zinkowski , PD Mehta , D Pratico , S Segal , C Clark , D Kerkman , J DeBernardis , J Li , L Lair , B Reisberg , W Tsui , H Rusinek (2004). MRI and CSF studies in the early diagnosis of Alzheimer's disease. Journal of Internal Medicine 256, 205223.

MJ de Leon , L Mosconi , J Li , S De Santi , Y Yao , WH Tsui , E Pirraglia , K Rich , E Javier , M Brys , L Glodzik , R Switalski , LA Saint Louis , D Pratico (2007 b). Longitudinal CSF isoprostane and MRI atrophy in the progression to AD. Journal of Neurology 254, 16661675.

C DeCarli , D Mungas , D Harvey , B Reed , M Weiner , H Chui , W Jagust (2004). Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia. Neurology 63, 220227.

T den Heijer , MI Geerlings , FE Hoebeek , A Hofman , PJ Koudstaal , MM Breteler (2006). Use of hippocampal and amygdalar volumes on magnetic resonance imaging to predict dementia in cognitively intact elderly people. Archives of General Psychiatry 63, 5762.

DP Devanand , G Pradhaban , X Liu , A Khandji , S De Santi , S Segal , H Rusinek , GH Pelton , LS Honig , R Mayeux , Y Stern , MH Tabert , MJ de Leon (2007). Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology 68, 828836.

C Eckerstrom , E Olsson , M Borga , S Ekholm , S Ribbelin , S Rolstad , G Starck , A Edman , A Wallin , H Malmgren (2008). Small baseline volume of left hippocampus is associated with subsequent conversion of MCI into dementia: the Goteborg MCI study. Journal of the Neurological Sciences 272, 4859.

M Ewers , K Buerger , SJ Teipel , P Scheltens , J Schroder , RP Zinkowski , FH Bouwman , P Schonknecht , NS Schoonenboom , N Andreasen , A Wallin , JF DeBernardis , DJ Kerkman , B Heindl , K Blennow , H Hampel (2007). Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI. Neurology 69, 22052212.

AM Fagan , CM Roe , C Xiong , MA Mintun , JC Morris , DM Holtzman (2007). Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Archives of Neurology 64, 343349.

A Fellgiebel , A Scheurich , P Bartenstein , MJ Muller (2007). FDG-PET and CSF phospho-tau for prediction of cognitive decline in mild cognitive impairment. Psychiatry Research 155, 167171.

AS Fleisher , S Sun , C Taylor , CP Ward , AC Gamst , RC Petersen , CR Jack Jr., PS Aisen , LJ Thal (2008). Volumetric MRI vs clinical predictors of Alzheimer disease in mild cognitive impairment. Neurology 70, 191199.

A Forsberg , H Engler , O Almkvist , G Blomquist , G Hagman , A Wall , A Ringheim , B Langstrom , A Nordberg (2008). PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiology of Aging 29, 14561465.

CJ Galton , S Erzinclioglu , BJ Sahakian , N Antoun , JR Hodges (2005). A comparison of the Addenbrooke's Cognitive Examination (ACE), conventional neuropsychological assessment, and simple MRI-based medial temporal lobe evaluation in the early diagnosis of Alzheimer's disease. Cognitive and Behavioral Neurology 18, 144150.

C Geroldi , R Rossi , C Calvagna , C Testa , L Bresciani , G Binetti , O Zanetti , GB Frisoni (2006). Medial temporal atrophy but not memory deficit predicts progression to dementia in patients with mild cognitive impairment. Journal of Neurology, Neurosurgery, and Psychiatry 77, 12191222.

JH Growdon (1999). Biomarkers of Alzheimer disease. Archives of Neurology 56, 281283.

AM Hall , RY Moore , OL Lopez , L Kuller , JT Becker (2008). Basal forebrain atrophy is a presymptomatic marker for Alzheimer's disease. Alzheimer's and Dementia 4, 271279.

H Hampel , K Burger , SJ Teipel , AL Bokde , H Zetterberg , K Blennow (2008). Core candidate neurochemical and imaging biomarkers of Alzheimer's disease. Alzheimer's and Dementia 4, 3848.

O Hansson , H Zetterberg , P Buchhave , E Londos , K Blennow , L Minthon (2006). Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurology 5, 228234.

SK Herukka , S Helisalmi , M Hallikainen , S Tervo , H Soininen , T Pirttila (2007). CSF Abeta42, Tau and phosphorylated Tau, APOE epsilon4 allele and MCI type in progressive MCI. Neurobiology of Aging 28, 507514.

JP Higgins , SG Thompson (2002). Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 21, 15391558.

G Karas , J Sluimer , R Goekoop , W van der Flier , SA Rombouts , H Vrenken , P Scheltens , N Fox , F Barkhof (2008). Amnestic mild cognitive impairment: structural MR imaging findings predictive of conversion to Alzheimer disease. AJNR. American Journal of Neuroradiology 29, 944949.

ES Korf , LO Wahlund , PJ Visser , P Scheltens (2004). Medial temporal lobe atrophy on MRI predicts dementia in patients with mild cognitive impairment. Neurology 63, 94100.

G Li , I Sokal , JF Quinn , JB Leverenz , M Brodey , GD Schellenberg , JA Kaye , MA Raskind , J Zhang , ER Peskind , TJ Montine (2007). CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study. Neurology 69, 631639.

J Lindeboom , B Schmand , L Tulner , G Walstra , C Jonker (2002). Visual association test to detect early dementia of the Alzheimer type. Journal of Neurology, Neurosurgery, and Psychiatry 73, 126133.

M Maruyama , T Matsui , H Tanji , M Nemoto , N Tomita , M Ootsuki , H Arai , H Sasaki (2004). Cerebrospinal fluid tau protein and periventricular white matter lesions in patients with mild cognitive impairment: implications for 2 major pathways. Archives of Neurology 61, 716720.

G McKhann , D Drachman , M Folstein , R Katzman , D Price , EM Stadlan (1984). 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 34, 939944.

JC Morris , DW McKeel Jr., K Fulling , RM Torack , L Berg (1988). Validation of clinical diagnostic criteria for Alzheimer's disease. Annals of Neurology 24, 1722.

L Mosconi , M Brys , L Glodzik-Sobanska , S De Santi , H Rusinek , MJ de Leon (2007). Early detection of Alzheimer's disease using neuroimaging. Experimental Gerontology 42, 129138.

RI Parker , S Hagan-Burke (2007). Useful effect size interpretations for single case research. Behavior Therapy 38, 95105.

L Parnetti , A Lanari , G Silvestrelli , E Saggese , P Reboldi (2006). Diagnosing prodromal Alzheimer's disease: role of CSF biochemical markers. Mechanisms of Ageing and Development 127, 129132.

RC Petersen , R Doody , A Kurz , RC Mohs , JC Morris , PV Rabins , K Ritchie , M Rossor , L Thal , B Winblad (2001). Current concepts in mild cognitive impairment. Archives of Neurology 58, 19851992.

RC Petersen , GE Smith , SC Waring , RJ Ivnik , EG Tangalos , E Kokmen (1999). Mild cognitive impairment: clinical characterization and outcome. Archives of Neurology 56, 303308.

R Rosenthal (1991). Meta-Analytic Procedures for Social Research. Sage: Newbury Park, CA.

H Rusinek , S De Santi , D Frid , WH Tsui , CY Tarshish , A Convit , MJ de Leon (2003). Regional brain atrophy rate predicts future cognitive decline: 6-year longitudinal MR imaging study of normal aging. Radiology 229, 691696.

P Schonknecht , J Pantel , E Kaiser , P Thomann , J Schroder (2007). Increased tau protein differentiates mild cognitive impairment from geriatric depression and predicts conversion to dementia. Neuroscience Letters 416, 3942.

LM Shaw , M Korecka , CM Clark , VM Lee , JQ Trojanowski (2007). Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics. Nature Reviews Drug Discovery 6, 295303.

I Skoog , P Davidsson , O Aevarsson , H Vanderstichele , E Vanmechelen , K Blennow (2003). Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds. Dementia and Geriatric Cognitive Disorders 15, 169176.

CD Smith , H Chebrolu , DR Wekstein , FA Schmitt , GA Jicha , G Cooper , WR Markesbery (2007). Brain structural alterations before mild cognitive impairment. Neurology 68, 12681273.

T Tapiola , C Pennanen , M Tapiola , S Tervo , M Kivipelto , T Hanninen , M Pihlajamaki , MP Laakso , M Hallikainen , A Hamalainen , M Vanhanen , EL Helkala , R Vanninen , A Nissinen , R Rossi , GB Frisoni , H Soininen (2008). MRI of hippocampus and entorhinal cortex in mild cognitive impairment: a follow-up study. Neurobiology of Aging 29, 3138.

E Tarkowski , N Andreasen , A Tarkowski , K Blennow (2003). Intrathecal inflammation precedes development of Alzheimer's disease. Journal of Neurology, Neurosurgery, and Psychiatry 74, 12001205.

SJ Teipel , C Born , M Ewers , AL Bokde , MF Reiser , HJ Moller , H Hampel (2007). Multivariate deformation-based analysis of brain atrophy to predict Alzheimer's disease in mild cognitive impairment. NeuroImage 38, 1324.

SG Thompson , JP Higgins (2002). How should meta-regression analyses be undertaken and interpreted? Statistics in Medicine 21, 15591573.

HC van Houwelingen , LR Arends , T Stijnen (2002). Advanced methods in meta-analysis: multivariate approach and meta-regression. Statistics in Medicine 21, 589624.

PN Wang , JF Lirng , KN Lin , FC Chang , HC Liu (2006). Prediction of Alzheimer's disease in mild cognitive impairment: a prospective study in Taiwan. Neurobiology of Aging 27, 17971806.

J Zaccai , P Ince , C Brayne (2006). Population-based neuropathological studies of dementia: design, methods and areas of investigation – a systematic review. BMC Neurology 6, 2.

KK Zakzanis (1998). Quantitative evidence for neuroanatomic and neuropsychological markers in dementia of the Alzheimer's type. Journal of Clinical and Experimental Neuropsychology 20, 259269.

KK Zakzanis , SJ Graham , Z Campbell (2003). A meta-analysis of structural and functional brain imaging in dementia of the Alzheimer's type: a neuroimaging profile. Neuropsychological Review 13, 118.

E Zamrini , S De Santi , M Tolar (2004). Imaging is superior to cognitive testing for early diagnosis of Alzheimer's disease. Neurobiology of Aging 25, 685691.

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