Biomarkers

Background: While the cerebrospinal fluid (CSF) biomarkers β-amyloid 1-42 (Aβ₄₂), β-amyloid 1-40 (Aβ₄₀), total tau (t-tau), and phosphorylated tau 181 (p-tau₁₈₁) can detect Alzheimer's disease (AD) pathology during life, there is a need to evaluate CSF cutpoints for specific application in Lewy body spectrum disorders (LBSD) in order to maximize detection to AD co-pathology. Using the Fujirebio LUMIPULSE G, we developed LBSD-derived cutpoints for CSF biomarkers and their ratios (Aβ₄₂/Aβ₄₀, p-tau₁₈₁/Aβ₄₂, t-tau/Aβ₄₂) to determine which best discriminates αSyn with AD (αSyn+AD) from αSyn without (αSyn). We compared our LBSD-derived cutpoints to the established AD-derived cutpoints.

Method: Participants were neuropathology-confirmed LBSD, with (αSyn+AD; n=24) or without AD co-pathology (αSyn; n=26). Amnestic AD without αSyn were included as a reference group (n=11). Receiver operating characteristic (ROC) and area under the curve (AUC) tested how accurately biomarkers discriminated between αSyn+AD and αSyn. Optimal cutpoints were identified by Youden's Index using bootstrapping (2000 iterations). Sensitivity, specificity, and accuracy were calculated at best cutpoints. Confidence intervals (95%CI) tested for differences between empirically-defined LBSD-specific cutpoints and previously established AD-derived cutpoints. Chi-square tests compared classification accuracy between LBSD- and AD-derived cutpoints. Survival analyses tested if biomarker status predicted time to death.

Result: Discriminating between αSyn and αSyn+AD, the CSF Aβ₄₂/Aβ₄₀ ratio had the highest accuracy (0.90), followed by p-tau₁₈₁/Aβ₄₂ ratio (0.87). We found that LBSD-derived cutpoints were higher than established AD-derived cutpoints for CSF Aβ₄₂/Aβ₄₀ ratio (0.080 [95%CI=0.069 - 0.089] vs. 0.058 pg/mL), and lower for CSF p-tau₁₈₁ (32.7 [95%CI=26.84 - 38.76] vs. 50.2 pg/mL) and t-tau (227 [95%CI=203.51- 278.66] vs. 409 pg/mL). Furthermore, LBSD-derived cutpoints identified individuals with AD co-pathology more accurately than the AD-derived cutpoints for CSF Aβ₄₂/Aβ₄₀ (X²= 23.26, P<0.001), p-tau₁₈₁ (X²=22.82, P<0.001) and t-tau (X²= 15.09, P<0.001). Survival analysis show that AD-positive individuals identified by the LBSD-derived CSF Aβ₄₂/Aβ₄₀ ratio cutpoint associate with earlier death (HR = 2.98, 95%CI = 0.41 - 1.77, P = 0.0017).

Conclusion: This study helps to establish AD CSF biomarkers for specific application in LBSD using the Fuijirebio LUMIPULSE G platform to maximize detection of AD co-pathology. Validation in an independent cohort is needed.