Modulating LRP1 Pathways in Alzheimer's Disease: Mechanistic Insights and Emerging Therapies

Globally, Alzheimer's disease (AD) is the leading cause of dementia. Key symptoms include extracellular amyloid β (Aβ) accumulation, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, and BBB disruption. Integrative solutions are needed because conventional medicines merely relieve symptoms and cannot stop disease progression. Low-density lipoprotein receptor-related protein 1 (LRP1) plays a crucial role in Aβ efflux, tau control, neuroinflammatory signaling, and neurovascular unit maintenance, making it a promising but unexplored therapeutic target. In AD and aging, LRP1 deficiency worsens clearance, vascular impairment, and neurodegeneration. Ligand-functionalized nanocarriers, antibodies, and gene manipulation show preclinical promise, but lower receptor expression, systemic off-target effects, and BBB penetration are challenges. Recent advances suggest innovative strategies, such as upregulating hepatic LRP1 for peripheral Aβ storage, modulating cofactors like ANKS1A (ankyrin repeat and SAM domain containing protein 1A) for receptor trafficking, using engineered nanoparticles or extracellular vesicles as Aβ decoys, preventing negative apolipoprotein E: ApoE4 and LRP1 interactions, and promoting neuroprotective pathways through LRP1 modulation. Endothelial-targeted gene therapy and dual transport rebalancing, which increases LRP1-mediated efflux and decreases RAGE-driven influx, are complementary. These precision strategies reposition LRP1 as a multifaceted therapeutic gateway rather than a clearance receptor, combining biomarker-driven patient stratification with next-generation delivery systems to transform AD disease-modifying therapies.