White Matter Hyperintensities Are No Major Confounder for Alzheimer's Disease Cerebrospinal Fluid Biomarkers

L.J.C. Van Waalwijk Van Doorn, M. Ghafoorian, E.M.C. Van Leijsen, J.A.H.R. Claassen, A. Arighi, M. Bozzali, J. Cannas, E. Cavedo, P. Eusebi, L. Farotti, C. Fenoglio, J. Fortea, G.B. Frisoni, D. Galimberti, V. Greco, S.-K. Herukka, Y. Liu, A. Lleó, A. De Mendonça, F.M. NobiliL. Parnetti, A. Picco, M. Pikkarainen, N. Salvadori, E. Scarpini, H. Soininen, R. Tarducci, A. Urbani, E. Vilaplana, O. Meulenbroek, B. Platel, M.M. Verbeek, H.B. Kuiperij, R. Martins

Research output: Contribution to journalArticlepeer-review


Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer's disease (AD). However, CSF biomarker levels can be affected by confounding factors. Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels. Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis. Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group. Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.

Original languageEnglish
Pages (from-to)163-175
Number of pages13
JournalJournal of Alzheimer's Disease
Issue number1
Publication statusPublished - 2021


  • Alzheimer's disease
  • amyloid
  • biomarkers
  • cerebrospinal fluid
  • magnetic resonance imaging
  • tau proteins
  • white matter hyperintensities
  • white matter lesions
  • amyloid beta protein[1-42]
  • biological marker
  • cell protein
  • phosphoprotein
  • tau protein
  • adult
  • Alzheimer disease
  • Article
  • automation
  • brain size
  • brain ventricle
  • comparative study
  • computer aided design
  • computer assisted diagnosis
  • controlled study
  • data analysis software
  • demography
  • detection algorithm
  • enzyme linked immunosorbent assay
  • female
  • human
  • image processing
  • image segmentation
  • lumbar puncture
  • machine learning
  • major clinical study
  • male
  • memory disorder
  • middle aged
  • mild cognitive impairment
  • neuroimaging
  • nuclear magnetic resonance imaging
  • prevalence
  • priority journal
  • protein cerebrospinal fluid level
  • standardization
  • white matter lesion


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