CSF biomarkers in Olmsted County Evidence of 2 subclasses and associations with demographics

Objective We studied interrelationships between CSF biomarkers and associations withAPOE epsilon 4 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 beta-amyloid 42 (A beta 42), total tau (t-tau), and hyperphosphorylated tau (p-tau) were analyzed using A beta 42 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 ofAPOE epsilon 4, demographic factors, cardiovascular risk, and diagnosis with CSF biomarker levels. Results were weighted back to the Olmsted County population. Results Interrelationships between CSF A beta 42 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 A beta 42 and p-tau (rho = 0.81), while the correlation was much smaller in group 2 (rho = 0.26, n = 227 [29%]). Group 2 was associated with older age,APOE epsilon 4 genotype, a diagnosis of MCI, and elevated amyloid PET. Overall,APOE epsilon 4 genotype and MCI were associated with A beta 42, 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 A beta 42 and p-tau/t-tau (represented also by the p-tau/t-tau/A beta 42 ratio). In those without biological AD, common factors such as CSF dynamics may cause a positive correlation between CSF A beta 42 and p-tau/t-tau, while AD leads to dissociation of these proteins.