Highlight
Obicetrapib, an oral cholesteryl ester transfer protein (CETP) inhibitor, significantly reduces plasma levels of the Alzheimer’s disease (AD) biomarker phosphorylated tau-217 (p-tau217) in patients with atherosclerotic cardiovascular disease (ASCVD), particularly in those carrying the high-risk ApoE4 allele. This substudy from the phase 3 BROADWAY trial reveals a potential novel preventive approach for AD in this vulnerable population. Obicetrapib also favorably modulates additional AD-related biomarkers, including the p-tau217/Aß42:40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), suggesting broader neuroprotective effects linked to CETP inhibition.
Background: Disease Burden and Rationale
Alzheimer’s disease presents a major public health challenge worldwide, with no definitive preventive therapies approved for those at high risk. Cardiovascular disease and Alzheimer’s share overlapping risk factors, and the apolipoprotein E4 (ApoE4) genotype represents a critical genetic determinant associated with increased risk of both ASCVD and AD. Dyslipidemia, especially elevated low-density lipoprotein cholesterol (LDL-C) and altered high-density lipoprotein cholesterol (HDL-C) profiles, contributes to pathophysiology in both diseases.
Recent advances suggest that cholesterol metabolism influences amyloid-beta (Aß) accumulation, tau phosphorylation, oxidative stress, and neuroinflammation—all hallmarks of AD. CETP inhibitors, initially developed to improve lipid profiles in cardiovascular disease, have emerged as promising candidates to modify AD risk by increasing HDL-C and improving HDL functionality, which may enhance amyloid clearance and reduce oxidative brain injury. Obicetrapib, a potent CETP inhibitor, effectively lowers LDL-C and raises HDL-C, paving the way to investigate its repurposed application for neuroprotection in ASCVD patients.
Study Design and Methods
The present substudy was embedded within the BROADWAY trial, a global phase 3, double-blind, placebo-controlled pivotal study evaluating the LDL-C lowering efficacy of obicetrapib in adults with established ASCVD and/or heterozygous familial hypercholesterolemia (HeFH) whose LDL-C remained elevated despite maximally tolerated lipid-lowering therapies. Conducted across 188 centers spanning China, Europe, Japan, and the United States from 2021 to 2024, 2530 participants were enrolled overall.
For this Alzheimer’s biomarker substudy, 1535 participants with known ApoE genotype and plasma p-tau217 measured at baseline and 12 months were analyzed. Participants were randomized 2:1 to receive either oral obicetrapib 10 mg daily or placebo for 12 months. Plasma AD biomarkers—p-tau217, p-tau181, the p-tau217/Aß42:40 ratio, GFAP, and NfL—were quantified using highly sensitive single molecule array (SIMOA) assays at baseline and study end.
Key Findings
The studied cohort had a median age of 67 years, and 67.0% were male. Baseline p-tau217 levels varied notably by ApoE genotype, with ApoE4 carriers exhibiting higher levels, and ApoE4/E4 individuals having the highest median p-tau217 concentration (0.56 pg/mL).
Over 12 months, obicetrapib treatment significantly attenuated the rise in plasma p-tau217 compared to placebo, with adjusted mean increases of 2.09% versus 4.94%, respectively (P = 0.025). Stratification by ApoE genotype uncovered pronounced benefits in ApoE4 carriers: obicetrapib limited mean p-tau217 increases to 1.92%, compared to 6.91% with placebo (P = 0.041). Remarkably, among ApoE4 homozygotes (ApoE4/E4), obicetrapib elicited a 7.81% adjusted mean decrease in p-tau217, contrasting with a 12.67% increase in the placebo group—a substantial –20.48% treatment difference (P = 0.010).
Secondary biomarkers corroborated these results. Obicetrapib significantly limited increases in the p-tau217/Aß42:40 ratio (2.51% vs 6.55%, P = 0.004), a key marker reflecting tau phosphorylation relative to amyloid pathology. In ApoE4/E4 subjects, significant reductions or attenuated rises were observed for GFAP (–6.39% vs +8.85%, P = 0.006) and NfL (–10.49% vs +6.82%, P = 0.020), markers indicative of astroglial activation and neuronal injury respectively.
Correlational analyses demonstrated a strong inverse relationship (r = –0.64) between plasma obicetrapib concentrations at study end and biomarker improvements, reinforcing CETP inhibition as the mechanistic driver, though pleiotropic effects cannot be excluded.
Expert Commentary
This pioneering work presents the first clinical evidence that an oral CETP inhibitor can modulate AD-specific plasma biomarkers, particularly p-tau217, a validated marker of tau pathology strongly predictive of clinical progression in AD. The findings are especially compelling in ApoE4 carriers, who bear the greatest genetic risk and for whom current effective preventive treatments are lacking.
From a mechanistic perspective, enhancing HDL quantity and quality—thereby promoting amyloid clearance, antioxidative capacity, and dampening neuroinflammatory cascades—can help explain obicetrapib’s effects. The reduction in GFAP and NfL signals suggests downstream neuroprotection beyond lipid effects alone.
Nevertheless, important questions remain. Biomarker improvements cannot substitute for clinical cognitive endpoints; thus, large dedicated AD prevention trials are needed to validate whether these biochemical changes translate into tangible cognitive and functional benefits. Moreover, longer follow-up will be essential to assess durability of effects and safety.
Limitations include the substudy nature within a cardiovascular trial population, potentially limiting generalizability outside ASCVD. The predominance of male subjects and median age near 67 years also underscores the need for diverse demographics in future studies.
Conclusion
The substudy of the BROADWAY trial provides robust evidence that obicetrapib, a potent CETP inhibitor, significantly slows progression of multiple plasma AD biomarkers over 12 months in patients with underlying cardiovascular disease. Benefits are magnified among ApoE4 carriers, particularly homozygotes, with a notable 20.48% placebo-adjusted reduction in p-tau217 levels and consistent attenuation of markers of amyloid pathology, astroglial activation, and neuronal injury.
These findings suggest CETP inhibition represents a promising therapeutic strategy for the prevention of AD in high-risk populations and justify further phase 3 trials with clinical endpoints focusing on cognition and disease progression. This innovative approach may fill a critical unmet need by offering a pharmacologic intervention that bridges cardiovascular and neurodegenerative disease risk reduction.
Funding and Trial Registration
The BROADWAY trial and its substudy were funded by the pharmaceutical sponsor developing obicetrapib. The Alzheimer’s biomarker substudy was prospectively specified to assess AD-related outcomes.
Trial registration: ClinicalTrials.gov Identifier: NCT05142722.
References
Davidson MH, Szarek M, Scheltens P, Vijverberg E, Hsieh A, Ditmarsch M, Kling D, Curcio D, Nicholls SJ, Ray KK, Cummings JL, Kastelein JJ. Effect of obicetrapib, a potent cholesteryl ester transfer protein inhibitor, on p-tau217 levels in patients with cardiovascular disease. J Prev Alzheimers Dis. 2025 Oct 17:100394. doi: 10.1016/j.tjpad.2025.100394. Epub ahead of print. PMID: 41109840.
