Obicetrapib, a CETP inhibitor, shows promise for reducing cardiovascular risk and potentially slowing Alzheimer's progression in APOE4 carriers. After four failed drugs in this class, this investigational therapy demonstrates robust LDL and lipoprotein(a) reduction plus intriguing biomarker signals in brain health—creating a coherent biological framework Peter Attia believes justifies urgent prevention trials. CETP inhibitors failed for decades because earlier versions either caused off-target toxicity or merely raised HDL without meaningfully lowering LDL and apoB, but obicetrapib achieves 50-60% additional LDL reduction on statin therapy plus 30% apoB reduction. In the BROADWAY trial's biomarker substudy, obicetrapib attenuated plasma phosphorylated tau-217 progression by 58% in APOE4 carriers over 12 months, with APOE4/4 individuals showing actual p-tau decline rather than increase.