The pathogenicity of PSEN2 variants is tied to Aß production and homology to PSEN1.

INTRODUCTION: Though recognized as a potential cause of Autosomal Dominant Alzheimer's Disease, the pathogenicity of many PSEN2 variants remains uncertain. We compared Aß production across all missense PSEN2 variants in the Alzforum database and, when possible, to corresponding PSEN1 variants. METHODS: We expressed 74 PSEN2 variants, 21 of which had homologous PSEN1 variants with the same amino acid substitution, in HEK293 cells lacking PSN1/2. Aß production was compared to age at symptom onset (AAO) and between homologous PSEN1/2 variants. RESULTS: Aß42/40 and Aß37/42 ratios were associated with AAO across PSEN2 variants, strongly driven by PSEN2 variants with PSEN1 homologs. PSEN2 AAO was 18.3 years later compared to PSEN1 homologs. Aß ratios from PSEN1 / 2 homologs were highly correlated, suggesting a similar mechanism of γ-secretase dysfunction. DISCUSSION: The existence of a PSEN1 homolog and patterns of Aß production are important considerations in assessing the pathogenicity of previously-reported and new PSEN2 variants.

Identification of Fibrinogen as a Plasma Protein Binding Partner for Lecanemab Biosimilar IgG: Implications for Alzheimer's Disease Therapy.

OBJECTIVE: Recombinant monoclonal therapeutic antibodies like lecanemab, which target amyloid beta in Alzheimer's disease, offer a promising approach for modifying the disease progression. Due to its relatively short half-life, Lecanemab, administered as a bi-monthly infusion (typically 10mg/kg) has a relatively brief half-life. Interaction with abundant plasma proteins binder in the bloodstream can affect pharmacokinetics of drugs, including their half-life. In this study we investigated potential plasma protein binding interaction to lecanemab using lecanemab biosimilar. METHODS: Lecanemab biosimilar used in this study was based on publicly available sequences. ELISA and Western blotting were used to assess lecanemab biosimilar immunoreactivity in the fractions human plasma sample obtained through size exclusion chromatography. The binding of lecanemab biosimilar to candidate binders was confirmed by Western blotting, ELISA, and surface plasmon resonance analysis. RESULTS: Using a combination of equilibrium dialysis, ELISA, and Western blotting in human plasma, we first describe the presence of likely plasma protein binding partner to lecanemab biosimilar, and then identify fibrinogen as one of them. Utilizing surface plasmon resonance, we confirmed that lecanemab biosimilar does bind to fibrinogen, although with lower affinity than to monomeric amyloid beta. CONCLUSION: In the context of lecanemab therapy, these results imply that fibrinogen levels could impact the levels of free antibodies in the bloodstream and that fibrinogen might serve as a reservoir for lecanemab. More broadly, these results indicate that plasma protein binding may be an important consideration when clinically utilizing therapeutic antibodies in neurodegenerative disease.