PLXNA4 (plexin A4) is a coreceptor for semaphorin-3A (SEMA3A) that functions primarily in axon guidance and neuronal development 1. The protein mediates semaphorin-plexin signaling through its cytoplasmic domain, modulating cytoskeletal remodeling and downstream signaling via FYN activation 1. Beyond developmental neurobiology, PLXNA4 has emerged as a critical regulator of cognitive function and neurodegeneration. It acts as a high-affinity receptor for clusterin (CLU) in the adult brain, with even 50% reduction in PLXNA4 levels causing memory impairments in mice 2. In Alzheimer's disease (AD), PLXNA4 expression is reduced by ~50% in affected brains, and specific isoforms regulate tau phosphorylation in an isoform-dependent manner 3. PLXNA4 polymorphisms associate with AD-related brain atrophy, particularly in the hippocampus, medial temporal lobe, and anterior cingulate, potentially through modulation of amyloid-β deposition and glucose metabolism 4. Additionally, PLXNA4 functions in vascular-neuronal communication; endothelial-derived SEMA3G signaling through neuropilin-2/PLXNA4 regulates hippocampal synaptic plasticity 5. Beyond AD, PLXNA4 modulates immune cell trafficking, negatively regulating cytotoxic T-cell infiltration into tumors through Rac1 activation 6, and rare variants associate with Parkinson's disease 7. These findings highlight PLXNA4's multifaceted roles in neurodegenerative disease pathogenesis.