CSF cutoffs for MCI due to AD depend on APOEε4 carrier status

Moira Marizzoni, Clarissa Ferrari, Claudio Babiloni, Diego Albani, Frederik Barkhof, Libera Cavaliere, Mira Didic, Gianluigi Forloni, Federica Fusco, Samantha Galluzzi, Tilman Hensch, Jorge Jovicich, Camillo Marra, José Luis Molinuevo, Flavio Nobili, Lucilla Parnetti, Pierre Payoux, Jean Philippe Ranjeva, Federica Ribaldi, Elena RolandiPaolo Maria Rossini, Marco Salvatore, Andrea Soricelli, Magda Tsolaki, Pieter Jelle Visser, Jens Wiltfang, Jill C. Richardson, Régis Bordet, Olivier Blin, Giovanni B. Frisoni

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)55-62
Number of pages8
JournalNeurobiology of aging
Early online date1 Jan 2020
Publication statusPublished - May 2020


  • Alzheimer's disease
  • Apolipoprotein E
  • CSF cutoff
  • Disease progression
  • Mild cognitive impairment

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