Cerebrospinal Fluid Biomarkers Distinguish Postmortem-Confirmed Alzheimer's Disease from Other Dementias and Healthy Controls in the OPTIMA Cohort

Abstract

Cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau have been studied as markers of Alzheimer's disease (AD). Combined Aβ₄₂ and t-tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up and postmortem evaluation to confirm clinicopathological status. Baseline CSF was analyzed from 227 participants with AD (97% autopsy-confirmed), mild cognitive impairment (MCI; 73% confirmed), other dementia syndrome (ODS; 100% confirmed), and controls (CTL; 27% confirmed, follow up approximately 9–13 years). Biomarker concentrations were analyzed using validated ELISAs. AD patients had lower CSF Aβ₄₂ and higher t-tau, p-tau, t-tau/Aβ₄₂, and t-tau/Aβ₄₀ compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aβ₄₀, sAβPPα, and sAβPPβ were lower in AD compared to CTL. High-level discriminators of AD from CTL were t-tau/Aβ₄₀ (AUROC 0.986, sens/spec of 92%/94%), p-tau/Aβ₄₂ (AUROC 0.972, sens/spec of 94%/90%), and Aβ₄₂ (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p-tau/Aβ₄₂ demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aβ₄₂ demonstrated sens/spec of 84%/100% (88%/100% at the AD versus CTL cutoff). In a well-characterized, homogeneous population, a single cutoff for baseline CSF Aβ and tau markers can distinguish AD with a high level of sens/spec compared to other studies. It may be important to characterize sources of demographic and biological variability to support the effective use of CSF diagnostic assays in the broader AD population.