Lipoprotein(a) is a genetic variant of low-density lipoprotein, approximately six times more atherogenic than traditional LDL. A normal LDL level does not exclude elevated Lp(a), which may contribute to persistent atherosclerotic risk. While its role in cardiovascular disease is well recognized, Lp(a) testing is rarely incorporated into neurologic evaluation despite emerging evidence linking elevated levels with stroke recurrence.

66-year-old African American male with PMHx of hypertension, hyperlipidemia, and diabetes experienced five ischemic strokes and one TIA between 2021 to 2024. Initial work-up after first stroke was significant for HbA1c of 8.3% and LDL of 157 mg/dL. MRA at this time demonstrated patent intracranial arteries with no evidence of atherosclerosis, aside from truncation of distal left M3 and distal cerebral arteries. Despite adherence to medication regimen, multiple subsequent admissions for additional strokes with radiographic evidence of multifocal involvement suspicious for embolic etiology. TEE identified a PFO, which was closed. Continuous rhythm monitoring via loop recorder showed no atrial fibrillation.

Extensive work-up for cryptogenic stroke was unrevealing except for markedly elevated Lp(a) at 161 mg/dL; guidelines recommend < 30 mg/dL. HbA1c was >7% during strokes but improved to 6.3% in 2025. Follow-up vascular imaging in 2025 demonstrated intracranial atherosclerotic disease present in the ACA, MCA, and PCA vessels with evidence of high-grade stenosis.

This case underscores elevated Lp(a) as a potential biomarker of residual risk for recurrent ischemic stroke despite structural correction of a PFO and appropriate medical management. Incorporating Lp(a) testing may enhance risk stratification, identify ICAD progression, and guide targeted secondary prevention with agents such as PCSK9 inhibitors, which are more effective than statins to lower Lp(a).