The APOE gene is the biggest genetic risk factor for Alzheimer's disease — but why the ε4 variant raises risk while the ε2 variant lowers it has remained a mystery. This large proteomics study analyzed thousands of proteins in blood and spinal fluid across five major research cohorts. The findings show that APOE2 upregulates proteins involved in cellular maintenance and anti-inflammatory processes, while APOE4 is linked to proteins reflecting vascular damage, immune dysfunction, and impaired protein clearance. Crucially, these protein signatures appear before any detectable Alzheimer's pathology and remain consistent across age and disease stage. The results identify specific molecular targets for allele-specific therapies — treatments tailored to a patient's particular APOE variant — and potential early biomarkers for clinical screening.
