CSF cutoffs for MCI due to AD depend on APOEε4 carrier status: Neurobiology of Aging

M. Marizzoni, C. Ferrari, C. Babiloni, D. Albani, F. Barkhof, L. Cavaliere, M. Didic, G. Forloni, F. Fusco, S. Galluzzi, T. Hensch, J. Jovicich, C. Marra, J.L. Molinuevo, F. Nobili, L. Parnetti, P. Payoux, J.-P. Ranjeva, F. Ribaldi, E. RolandiP.M. Rossini, M. Salvatore, A. Soricelli, M. Tsolaki, P.J. Visser, J. Wiltfang, J.C. Richardson, R. Bordet, O. Blin, G.B. Frisoni

Research output: Contribution to journalArticlepeer-review


Amyloid and tau pathological accumulation should be considered for Alzheimer's disease (AD) definition and before subjects' enrollment in disease-modifying trials. Although age, APOEε4, and sex influence cerebrospinal fluid (CSF) biomarker levels, none of these variables are considered by current normality/abnormality cutoffs. Using baseline CSF data from 2 independent cohorts (PharmaCOG/European Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Neuroimaging Initiative), we investigated the effect of age, APOEε4 status, and sex on CSF Aβ42/P-tau distribution and cutoff extraction by applying mixture models with covariates. The Aβ42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cutoffs. The identification of the intermediate subgroup and of the higher cutoff was APOEε4 dependent in both cohorts. APOE-specific classification (higher cutoff for APOEε4+, lower cutoff for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aβ42 and Aβ42/P-tau cutoffs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE-specific cutoffs to identify MCI due to AD and ii) the utility of considering APOE genotype for early AD diagnosis. © 2020 Elsevier Inc.
Original languageEnglish
Pages (from-to)55-62
Number of pages8
JournalNeurobiol. Aging
Publication statusPublished - 2020


  • Alzheimer's disease
  • Apolipoprotein E
  • CSF cutoff
  • Disease progression
  • Mild cognitive impairment
  • amyloid beta protein[1-42]
  • apolipoprotein E
  • apolipoprotein E epsilon4
  • tau protein
  • unclassified drug
  • amyloid beta protein
  • amyloid beta-protein (1-42)
  • biological marker
  • peptide fragment
  • age distribution
  • aged
  • Alzheimer disease
  • Article
  • brain atrophy
  • cerebrospinal fluid
  • cohort analysis
  • controlled study
  • diagnostic accuracy
  • diagnostic test accuracy study
  • early diagnosis
  • female
  • genotype
  • heterozygote
  • hippocampus
  • human
  • major clinical study
  • male
  • mild cognitive impairment
  • neuroimaging
  • priority journal
  • protein cerebrospinal fluid level
  • receiver operating characteristic
  • sensitivity and specificity
  • sex difference
  • validity
  • white matter lesion
  • cognitive defect
  • complication
  • genetics
  • very elderly
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Biomarkers
  • Cognitive Dysfunction
  • Cohort Studies
  • Female
  • Heterozygote
  • Humans
  • Male
  • Peptide Fragments
  • tau Proteins


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