Related Experiment Video
Updated: Dec 17, 2025
Author Spotlight: Integrated Multi-Omics Analysis for Unveiling Multicellular Immune Signatures in Clinical Heart Attack Cohorts
Published on: September 20, 2024
CSF biomarkers in Olmsted County: Evidence of 2 subclasses and associations with demographics
Argonde C Van Harten1, Heather J Wiste2, Stephen D Weigand2
1From the Departments of Neurology (A.C.V.H., M.M.M., D.S.K., R.C.P.), Health Sciences Research (H.J.W., S.D.W., M.M.M., W.K.K., R.C.P.), Laboratory Medicine and Pathology (R.B.D.), and Radiology (C.R.J.), Mayo Clinic, Rochester, MN; Department of Neurology and Alzheimer Center Amsterdam UMC (A.C.V.H.), the Netherlands; and Roche Diagnostics (U.E., R.B.-U., A.A.-S.), Basel, Switzerland. VanHarten.Argonde@mayo.edu.
Objective:
We studied interrelationships between CSF biomarkers and associations with APOE ε4 genotype, demographic variables, vascular variables, and clinical diagnosis in Olmsted County, Minnesota.
Methods:
We included 774 Mayo Clinic Study of Aging participants (693 cognitively unimpaired [CU]; 71 with mild cognitive impairment [MCI]). CSF β-amyloid 42 (Aβ42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using Aβ42 CSF, t-tau CSF, and p-tau (181P) CSF electrochemiluminescence immunoassays. Bivariate mixture models were used to evaluate latent classes. We used linear regression models to evaluate independent associations of APOE ε4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population.
Results:
Interrelationships between CSF Aβ42 and p-tau/t-tau were consistent with 2 latent classes in the general population. In subgroup 1 (n = 547 [71%]), we found a strong positive correlation between Aβ42 and p-tau (ρ = 0.81), while the correlation was much smaller in group 2 (ρ = 0.26, n = 227 [29%]). Group 2 was associated with older age, APOE ε4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall, APOE ε4 genotype and MCI were associated with Aβ42, while age was associated with p-tau/t-tau. There were no associations with sex, education, or vascular risk.
Conclusion:
We hypothesize the population without dementia can be subdivided into participants with and without biological Alzheimer disease (AD) based on the combination of CSF Aβ42 and p-tau/t-tau (represented also by the p-tau/t-tau/Aβ42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF Aβ42 and p-tau/t-tau, while AD leads to dissociation of these proteins.
Insights
Two distinct groups of individuals were identified based on cerebrospinal fluid (CSF) biomarkers, suggesting potential biological differences in Alzheimer's disease (AD) progression and risk factors like APOE ε4 genotype.
Area of Science:
- Neuroscience
- Biomarker Research
- Aging Studies
Background:
- Understanding cerebrospinal fluid (CSF) biomarkers is crucial for diagnosing and tracking neurodegenerative diseases.
- Interactions between amyloid-beta 42 (Aβ42) and tau (t-tau, p-tau) levels offer insights into Alzheimer's disease (AD) pathology.
- The APOE ε4 genotype is a known risk factor for AD.
Purpose of the Study:
- To investigate the relationships between CSF biomarkers (Aβ42, t-tau, p-tau) and their associations with APOE ε4 genotype, demographics, vascular factors, and clinical diagnosis.
- To identify distinct subgroups within a population based on CSF biomarker profiles.
- To explore the potential for differentiating biological AD from other conditions using CSF biomarker patterns.
Main Methods:
- Analysis of CSF Aβ42, t-tau, and p-tau levels in 774 participants from the Mayo Clinic Study of Aging.
- Utilized bivariate mixture models to identify latent classes based on CSF biomarker interrelationships.
- Employed linear regression models to assess associations with APOE ε4, demographics, cardiovascular risk, and diagnosis.
Main Results:
- Two distinct latent classes of CSF biomarker profiles were identified.
- Class 1 showed a strong positive correlation between Aβ42 and p-tau (ρ = 0.81), while Class 2 had a weaker correlation (ρ = 0.26).
- Class 2 was associated with older age, APOE ε4 genotype, mild cognitive impairment (MCI), and elevated amyloid PET; APOE ε4 and MCI correlated with Aβ42, while age correlated with p-tau/t-tau.
Conclusions:
- The findings support the hypothesis that the population can be subdivided based on CSF Aβ42 and p-tau/t-tau levels, potentially distinguishing biological AD.
- CSF dynamics may explain the positive correlation in non-AD groups, whereas AD may lead to dissociation of these biomarkers.
- These CSF biomarker patterns may aid in understanding disease mechanisms and stratifying individuals for research and clinical purposes.
