CSF cutoffs for MCI due to AD depend on APOEε4 carrier status
Moira Marizzoni1, Clarissa Ferrari2, Claudio Babiloni3
1Laboratory of Neuroimaging and Alzheimer's Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Abstract:
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.
Insights
Alzheimer's disease (AD) diagnosis can be improved by using APOEε4-specific cutoffs for cerebrospinal fluid (CSF) biomarkers amyloid and tau. These APOEε4-adjusted cutoffs enhance the accuracy in identifying mild cognitive impairment (MCI) due to AD.
Area of Science:
- Neurology
- Biomarker Research
- Gerontology
Background:
- Alzheimer's disease (AD) diagnosis and clinical trial enrollment rely on amyloid and tau pathology.
- Current cerebrospinal fluid (CSF) biomarker cutoffs do not account for age, sex, or APOEε4 status.
- APOEε4 genotype is a significant risk factor influencing AD progression.
Purpose of the Study:
- To investigate the impact of age, sex, and APOEε4 status on CSF Aβ42/P-tau distribution and cutoffs.
- To develop and validate APOEε4-specific cutoffs for improved AD diagnosis.
- To assess the diagnostic accuracy of APOEε4-specific cutoffs in identifying mild cognitive impairment (MCI) due to AD.
Main Methods:
- Analysis of baseline CSF data from two independent cohorts (PharmaCOG/EADB-NI and ADNI).
- Application of mixture models with covariates to determine CSF Aβ42/P-tau distribution and extract cutoffs.
- Comparison of diagnostic accuracy between APOEε4-specific cutoffs and standard cutoffs for Aβ42 and Aβ42/P-tau.
Main Results:
- CSF Aβ42/P-tau distribution identified three subgroups: AD-like, intermediate, and control-like, with two distinct cutoffs.
- The intermediate subgroup and the higher cutoff were dependent on APOEε4 status in both cohorts.
- APOEε4-specific classification demonstrated superior diagnostic accuracy for MCI due to AD compared to single cutoffs.
Conclusions:
- APOEε4 genotype significantly influences amyloid and tau CSF markers and AD progression in MCI patients.
- The study supports the use of APOEε4-specific cutoffs for accurate identification of MCI due to AD.
- Incorporating APOE genotype into early AD diagnosis using CSF biomarkers is recommended.
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