Blocking the p21-activated kinase 1 (PAK1) enzyme with compound NVS-PAK1-1 prevented synapse destruction in neurons exposed to toxic Alzheimer's proteins, achieving protection at just 2 nanomolar concentrations. The inhibitor demonstrated oral bioavailability and brain penetration in transgenic mice, reducing PAK1 hyperactivation while preserving dendritic spine density and normalizing synaptic protein profiles in female animals. This represents a potentially significant advance in Alzheimer's therapeutics, as synaptic spine loss directly correlates with cognitive decline and occurs early in disease progression. Unlike approaches targeting amyloid plaques or tau tangles themselves, PAK1 inhibition addresses downstream synaptic damage that may be more reversible. The strategy aligns with growing recognition that preserving existing neural connections may be more achievable than clearing protein aggregates. However, the sex-specific efficacy observed only in female mice raises questions about hormonal influences and broader applicability. The nanomolar potency suggests strong target engagement, but long-term safety and cognitive outcomes remain to be established. If replicated in human trials, PAK1 inhibition could offer a novel neuroprotective approach distinct from current amyloid-focused strategies.