Experimental Alzheimer’s Drug Slows Biomarker Progression in Early Trial
A cholesterol-lowering CETP inhibitor shows early promise for Alzheimer’s patients carrying APOE4
Obicetrapib, an experimental CETP inhibitor already known for lowering LDL cholesterol and raising HDL cholesterol in cardiovascular disease, slowed progression of a key Alzheimer’s biomarker (p-tau217) over 12 months. The effect was most notable in APOE4 carriers, who are at highest risk for both cardiovascular disease and Alzheimer’s.
Study Details
The findings, presented at the Alzheimer’s Association International Conference (AAIC) 2025, came from an analysis of the BROADWAY trial. Originally designed to test lipid-lowering effects in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia, the study offered a unique opportunity to measure Alzheimer’s biomarkers in a high-risk population.
Researchers analyzed data from 1515 participants, average age 66–70, of whom 21% carried the APOE4 genotype. Many participants also had diabetes (37.8%) and hypertension (84.7%), typical of a cardiovascular population.
Methodology
Patients received 10 mg obicetrapib or placebo daily for 12 months, in addition to maximally tolerated lipid-lowering therapy.
Alzheimer’s biomarkers were measured at baseline and after 12 months, including p-tau217 (primary outcome), p-tau181, amyloid-beta 42/40 ratio, GFAP, and neurofilament light chain (NFL).
Key Findings
p-tau217: Obicetrapib group showed 1.99% mean change vs 4.98% in placebo (P = .0188), suggesting slower progression.
APOE4 homozygotes: Saw a striking 20% relative reduction in p-tau217 compared with placebo, though this subgroup was very small (n=29).
Other biomarkers (p-tau181, GFAP, NFL, amyloid-beta ratio) showed modest, non-significant differences.
Cholesterol effects: LDL cholesterol dropped 33% and HDL cholesterol rose significantly in the treatment group.
Safety: Obicetrapib was well tolerated, with adverse event rates similar to placebo (~60%).
Implications for Practice
For patients: If validated, obicetrapib may become a dual-action therapy, protecting both heart and brain. This is particularly meaningful for older adults with cardiovascular disease who carry APOE4, a major genetic risk factor for Alzheimer’s.
For clinicians: Traditional statins have shown no clear benefit in Alzheimer’s, but CETP inhibition may represent a new therapeutic path by linking lipid metabolism to Alzheimer’s pathology.
Next steps: Larger phase 3 trials in patients with mild cognitive impairment due to Alzheimer’s will be critical to confirm whether biomarker improvements translate into slower cognitive decline.