Genetic liability to hip osteoarthritis confers neurovascular protection against Alzheimer's disease despite depression-mediated phenotypic comorbidity

Abstract

Background: The relationship between hip osteoarthritis (hip OA) and Alzheimer's disease (AD) presents a critical paradox within the emerging "bone-brain axis": widespread phenotypic comorbidity sharply contradicts evolutionary theories of biological antagonism. This study integrates longitudinal and multi-omic analyses to determine whether this clinical overlap masks an underlying genetic neuroprotection. Methods: We analyzed longitudinal phenotypic data from 261,767 UK Biobank participants using Cox proportional hazards and Fine-Gray competing risk models. To investigate the shared genetic architecture, we applied MiXeR modeling to genome-wide association study summary statistics. Causal relationships were evaluated using global and cell-type-stratified Mendelian randomization across eight distinct brain cell types. Shared genomic loci were identified via conjunctional/conditional false discovery rate and fine-mapping. Single-nucleus RNA-sequencing (snRNA-seq) data from the ROSMAP cohort validated the disease-associated transcriptional dynamics of prioritized target genes. Results: Observational survival analyses initially suggested an increased AD risk in patients with hip OA; however, this association was fully attenuated after adjusting for a history of depression, revealing a "phenotypic illusion" driven by the pain-depression axis. Conversely, cell-type-stratified genomic analyses uncovered a profound biological antagonism: genetic liability for hip OA confers robust neuroprotection specifically localized to the neurovascular unit (NVU), primarily driven by astrocytes and pericytes. Mechanistically, this NVU fortification is orchestrated by the MAPT locus and PI3K/AKT signaling, with snRNA-seq confirming the active transcriptional remodeling of these core effectors in the AD brain. Conclusion: We demonstrate that genetic liability to hip OA confers robust neurovascular protection against AD, a profound biological antagonism that is clinically masked by depression-mediated phenotypic comorbidity. These findings propose an evolutionary trade-off model within the bone-brain axis, underscoring the urgency of active hip OA pain management to mitigate depressive symptoms and decelerate cognitive aging, while cautioning against the uncritical repurposing of anabolic inhibitors across these interconnected systems.