To improve screening performances by excluding regressive PSA and low-risk positive progression in FR(−)/LR(−), optimized screening strategy not only significantly reduce 32.4% of missed PCa (54.0% [1881/3484] vs. 21.6% [754/3484], P < 0.001), but also detected additional 8.0% of high-grade PCa (Gleason score 7–10: 36.0% [665/1849] vs. 28.0% [206/736], P < 0.001) than traditional screening strategy. The gene discussed is KLK3; the disease is posterior cortical atrophy.