We identified three SNP–SNP interaction pairs significantly associated with PCa aggressiveness: rs1801133 (MTHFR)-rs2236225 (MTHFD1) and rs1801131 (MTHFR)-rs7587117 (SLC4A5) for EAs and DHFR-19bp-rs4652 (LGALS3) for AAs. Here, SLC4A5 is linked to posterior cortical atrophy.