Prescription-based association of P-glycoprotein substrates with Alzheimer's disease risk: A nested case-control study.

BackgroundP-glycoprotein (P-gp) is linked to Alzheimer's disease (AD), as P-gp contributes to clearance of amyloid-β (Aβ) from the CNS. Thus, other P-gp substrates (Pgp-S) could affect Aβ clearance, either negatively through competitive inhibition or positively via cooperative transport, impacting risk for AD.ObjectiveWe probed impacts of Pgp-S on AD risk by querying AD rates among individuals prescribed medications that are considered Pgp-S.MethodsA retrospective cohort study was performed using the PharMetrics Plus database (IQVIA), encompassing 70,340 users of prescription drugs identified as Pgp-S and 352,382 Pgp-S non-users. Users and non-users were matched by age, sex, and geographical region. Cox regression models afforded adjustments for covariates and comorbidities.ResultsPgp-S use was generally associated with a significant reduction in the hazard ratio of AD in both crude (HR = 0.89, 95% CI = 0.79-0.99) and matched (HR = 0.87; 95% CI = 0.78-0.98) analyses. AD risk was higher among subsets diagnosed with comorbidities: depression (HR = 4.44; 95% CI, 3.99-4.94), stroke (HR = 1.98, 95% CI = 1.63-2.41), and hypertension (HR = 1.24, 95% CI = 1.13-1.36). In an analysis of individual drugs, digoxin (OR = 0.52, 95% CI, 0.34-0.77), atorvastatin (OR = 0.80, 95% CI, 0.73-0.87), omeprazole (OR = 0.83, 95% CI, 0.73-0.94), and prednisone (OR = 0.64, 95% CI, 0.46-0.86) were associated with significantly decreased odds of incident AD; rivaroxaban (OR = 1.29, 95% CI = 0.97-1.68) and mirabegron (OR = 1.45, 95% CI = 0.86-2.28) trended toward increased risk.ConclusionsThe findings suggest an association between Pgp-S use and AD, but limitations of the study design impel additional work to confirm the direction of impact for individual drugs.