Pharmacodynamic and stage-dependent therapeutic efficacy of SFRP1 neutralization in a mouse model of Alzheimer s disease

Alzheimers disease (AD) is characterized by early synaptic dysfunction followed by progressive amyloid-{beta} (A{beta}) accumulation, neuroinflammation, and cognitive decline. We previously identified Secreted Frizzled-Related Protein 1 (SFRP1) as a multifactorial contributor to AD pathogenesis and provided initial evidence that its neutralization ameliorates pathological AD-like traits in mice. Here, we evaluate the pharmacodynamics, biodistribution, and therapeutic window of an -SFRP1 monoclonal antibody (-SFRP1) in APP/PS1 mice. Pharmacokinetics and target engagement of -SFRP1 were assessed in different groups of APP/PS1 mice using biotinylated or 89Zr-labelled antibodies, with tissue distribution and -SFRP1 levels quantified by in-house ELISA or PET/CT. Therapeutic efficacy was evaluated by administering -SFRP1 or the SFRP1 inhibitor WAY-316606 at different stages of disease progression via retro-orbital injection, followed by analysis of AD-like pathology using ELISA and immunofluorescence assays followed by quantifications and statistical analysis. Using 89Zr-labelled antibodies, we show that intravenously administered -SFRP1 engages its target systemically and reaches the brain, although at substantially lower levels and with a rapid 24-hour clearance. Treatment with -SFRP1 had no apparent systemic side effects, but its therapeutic efficacy against AD-like brain pathology was strongly dependent on disease stage. While early administration reduced amyloid pathology in previous studies, treatment initiated at intermediate or advanced stages showed minimal benefit at standard doses. Higher antibody doses reduced amyloid burden and dystrophic neurites but were associated with increased mortality with time. Pharmacological inhibition of SFRP1 using a small-molecule inhibitor similarly failed to ameliorate pathology at intermediate stages. Together, these findings demonstrate that SFRP1 remains a relevant therapeutic target in AD, but its effective modulation is constrained by limited brain exposure and a narrow therapeutic window, underscoring the importance of early intervention and prompting the search for improved brain-targeted delivery strategies.