P2‐067: Modifications in Albumin Molecular Profile in a Phase 2 Study Based on Therapeutic Plasma Exchange and 5% Albumin Replacement in Alzheimer's Disease

Pilot and Phase II studies using total plasma exchange (TPE) with albumin replacement in Alzheimer’s disease (AD) showed encouraging results that lead to initiate a Phase IIB/III study (AMBAR, NCT01561053). With TPE, beta amyloid (Aβ) and other substances are removed, while impaired albumin is replaced with Aβ-free albumin (Albutein®, Grifols). Aβ removal can shift the equilibrium from CSF to plasma, while albumin renewal can provide antioxidant and binding capacity. In this study we analyze albumin molecular changes in plasma from Phase II AD patients during treatment. Forty-two AD patients (randomized 1:1 TPE-treated/sham TPE-treated), received 2 TPE/week-3 weeks (Intensive period), followed by one TPE/weekly- 6 weeks (Maintenance I), one TPE/biweekly-12 weeks (Maintenance II) plus 24-week follow-up. Plasma samples were obtained at baseline (n=30/42) and before/after TPE (n=6/21 treated, n=6/21 non-treated patients). Age-matched healthy controls (HC) (n=30) were also evaluated. Oxidized status of albumin Cys34 thiol group was analyzed by anionic-exchange chromatography. Post-translational modifications were analyzed by ultra-high performance liquid chromatography coupled to mass spectrometry (MS). Plasma Aβ levels were determined by ELISA. Albumin oxidation status at baseline in AD patients showed increased reversibly oxidized albumin when compared with HC (40.08% [40.08%-47.35%] vs 36.36% [36.36%-38.32%]; median-IQR, p<0.01). This increment mainly relies on cysteinylated form as confirmed by MS. When samples were analyzed during treatment, a modification on the albumin oxidation was evident only in the treated group. Thus, levels of irreversibly oxidized albumin increased progressively during intensive period of treatment from 3.03 [3.03-3.2] % at baseline up to 11.37% [11.37%-14.45%] (median-IQR; p<0.05) before the last PE; while untreated group did not show any change. This effect was associated with the treatment intensity and, interestingly, correlated with Aβ mobilization observed in plasma after TPE in the same Phase II study (r=0.6022; p<0.0001). Albumin from AD patients is impaired, at least in its antioxidant capacity, in comparison with healthy subjects. TPE with albumin replacement in AD patients seems to have an effect on albumin oxidation status that correlates with plasma Aβ mobilization. Further investigation is warranted to better understand the mechanisms underlying AD therapy based on TPE followed by albumin replacement.