The role of APOE4 in Alzheimer's disease: strategies for future therapeutic interventions

This review sits a little apart from the cardiovascular core — its subject is APOE4 and Alzheimer’s disease — but the gene matters here because the same apolipoprotein E governs how the body handles lipids, and APOE4 is a shared thread between brain and vascular risk.

The authors detail how the APOE4 variant, the strongest common genetic risk factor for late-onset Alzheimer’s, drives disease through several routes: promoting amyloid-beta aggregation and tau phosphorylation, impairing mitochondrial function, and disrupting insulin signaling. They then survey therapeutic strategies aimed at modulating APOE4 or its downstream effects, particularly improving cellular cleanup (autophagy) and mitochondrial health.

The practical takeaway is forward-looking: APOE4-targeted interventions could one day delay or prevent Alzheimer’s in the large at-risk carrier population, though none are yet established. The resistance comes from a field heavily committed to amyloid-targeting drugs.

We rate the evidence moderate: a comprehensive, 144-reference synthesis with no declared conflicts, but a narrative review of mechanisms rather than a trial. Its clinical significance is moderate and potential — APOE4 carriers are a huge population, but translation into approved therapies is still ongoing. For our readers, its main value is the reminder that the genetics of lipid handling reach beyond the heart.