Lipoprotein(a) and risk of dementia: A propensity score–matched real-world analysis from a global federated research network

BACKGROUND: The association between lipoprotein(a) [Lp(a)] and dementia remains controversial. PURPOSE: To assess the relationship between Lp(a) and dementia in a global federated research network. METHODS: A retrospective cohort study using data from the TriNetX network. Adults with at least one Lp(a) measurement from 2010 onward were categorized as having elevated (≥50 mg/dL) or normal (<50 mg/dL) Lp(a). Propensity score matching (1:1) balanced baseline characteristics. The primary outcome was incident all-cause dementia; secondary outcomes included Alzheimer's disease, vascular dementia, and frontotemporal dementia. Follow-up extended up to 10 years from the index Lp(a) measurement. Sensitivity analyses accounted for death as a competing event, a 30-day landmark analysis, and comparison across low, high, and very high Lp(a) levels. Subgroup analyses were performed by age, sex, and history of atherosclerotic cardiovascular disease or stroke. RESULTS: Of 151,117 patients with available Lp(a) data, 54,929 had elevated Lp(a) (mean age 56.5 ± 15.9 years; 53.2% female), while 96,188 had normal Lp(a) (mean age 56.4 ± 16.5 years; 48.4% female). After matching, each cohort included 54,841 patients. Over a maximum follow-up of 10 years, elevated Lp(a) was not associated with an increased risk of all-cause dementia (HR 0.99, 95% CI 0.88-1.10), Alzheimer's disease (HR 1.04, 95% CI 0.85-1.27), vascular dementia (HR 1.05, 95% CI 0.86-1.27), or frontotemporal dementia (HR 0.94, 95% CI 0.48-1.83). Findings were consistent across sensitivity and subgroup analyses. CONCLUSION: In this large real-world cohort, elevated Lp(a) levels were not significantly associated with an increased risk of incident dementia or its major subtypes.