Repurposing probucol for prevention of dementia: Evidence from a nationwide cohort study

BACKGROUNDEffective treatments for neurodegenerative diseases remain elusive, underscoring the importance of preventive strategies. Probucol, a cholesterol lowering and antioxidant drug with established cardiovascular use, has shown neuroprotective effects in preclinical models of dementia by modulating peripheral lipoprotein amyloid metabolism and preserving capillary integrity. However, no large-scale human studies have examined its association with dementia risk. OBJECTIVETo examine the association between probucol use and incident dementia in older adults. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study used the Japan Medical Data Centre claims database from 2014 to 2023. Adults aged 50 years or older prescribed probucol or statins were included, excluding those with prior dementia or recent drug exposure. Participants were categorized as probucol monotherapy users, statin monotherapy users, or combination users ([≥]2 prescriptions). Propensity score matching was used to balance baseline comorbidities. EXPOSURESProbucol or statin therapy. MAIN OUTCOMES AND MEASURESThe primary outcome was incident all cause dementia. Secondary outcomes included Alzheimers disease and mixed Alzheimers and vascular dementia. Odds ratios (ORs) with 95% CIs were calculated using logistic regression adjusted for age and sex. RESULTSAmong 57 231 individuals (52.6% female) followed for up to 10 years (median, 3 years), 7 387 (12.9%) developed dementia. The cohort included 2 896 probucol users (5.1%) and 54 335 statin users (94.9%). Dementia incidence was higher among females (14.7%) than males (10.9%). Dementia incidence was lower in probucol users (5.6%, 162/2 896) than in statin users overall (13.2%, 8 248/62 519), with individual statins ranging from 11.4% (fluvastatin) to 16.7% (pravastatin). Probucol use was associated with a 62% lower adjusted risk of dementia compared with all statin users combined (adjusted OR, 0.38; 95% CI, 0.37-0.38). Protective associations were consistent across individual statin comparisons, with adjusted ORs ranging from 0.30 (pitavastatin) to 0.57 (fluvastatin). CONCLUSIONS AND RELEVANCEIn this large national cohort of Japanese adults, probucol use was associated with a substantially lower risk of incident dementia compared with statins. These findings provide the first large-scale human evidence linking probucol exposure with reduced dementia risk, supporting its further evaluation as a preventive therapy in prospective clinical trials. Key PointsO_ST_ABSQuestionC_ST_ABSIs use of the lipid-lowering and antioxidant agent probucol associated with a reduced risk of incident dementia compared with statin therapy in older adults? FindingsIn this nationwide cohort study of 57 231 Japanese adults aged 50 years and older, dementia incidence was nearly halved in probucol users (5.6%) compared with statin users overall (13.2%), corresponding to 62% lower adjusted odds of dementia. Protective associations were consistent across dementia subtypes and individual statins. MeaningThese findings suggest that probucol, a long-standing and well-tolerated cardiovascular drug, may offer a mechanistically distinct and potentially scalable strategy for dementia prevention, warranting confirmation in prospective intervention trials.