Lipid-Lowering Med Heads to Alzheimer’s Prevention Trial in APOE4 Carriers

 A post hoc analysis of a phase 3 trial suggested the lipid-lowering drug obicetrapib may have its greatest effect on the Alzheimer’s disease (AD) biomarker phosphorylated tau 217 (p-tau217) in APOE4 carriers, with new findings that are helping to shape a planned Alzheimer’s prevention trial.

Researchers are digging deeper into why APOE4 carriers appear to derive the greatest biomarker benefit from obicetrapib and how those findings can help identify the patients most likely to benefit in future AD prevention trials.

The latest analysis identified the APOE4 carriers most likely to respond to obicetrapib, findings that will help shape a planned Alzheimer’s prevention trial enriched for these high-risk patients.

“We want to see whether there’s actually a preventive effect,” Philip Scheltens, MD, PhD, partner and head of the Dementia Fund, EQT Group, Amsterdam, Netherlands, told Medscape Medical News.

The study results were presented on July 13 at the Alzheimer’s Association International Conference (AAIC) 2026.

The BROADWAY study was a phase 3, randomized, double-blind, placebo-controlled trial evaluating the effect of 10 mg of obicetrapib as an adjunct to maximally tolerated lipid-lowering therapy over 1 year in patients with cardiovascular disease.

Results showed the intervention reduced low-density lipoprotein (LDL) cholesterol levels by 29.9%.

The biomarker substudy, presented at AAIC 2025, included 1535 participants with known APOE status, including 367 APOE4 carriers. The analysis showed obicetrapib reduced p-tau217, with the greatest effect in APOE4 carriers.

Among participants with two APOE4 alleles (E4/E4), p-tau217 levels were 20.5% lower than among those receiving placebo.

“This shows that the APO[E]4s are the ones who have an impaired cholesterol metabolism in the brain and would benefit most from CETP inhibition,” said Scheltens.

A separate analysis presented at this year’s AAIC helped explain why investigators focused on APOE4 carriers in the current study. Nearly half (45.9%) of the participants in the BROADWAY biomarker substudy had p-tau217 levels above the threshold associated with preclinical AD (0.42 pg/mL), and APOE4 carriers were disproportionately represented among those with the highest p-tau217 levels (> 0.62 pg/mL), suggesting established AD pathology.

Compared with other p-tau biomarkers, p-tau217 offers greater sensitivity and specificity for AD pathology, Scheltens said. “It’s a good marker for Alzheimer’s pathology in the broadest sense because it reflects amyloid as well as tau,” he added.

In a separate presentation at this year’s conference, investigators identified several factors associated with higher p-tau217 levels in BROADWAY participants. In addition to APOE4 carrier status, older age, a history of diabetes, and lower estimated glomerular filtration rate were independently associated with higher biomarker levels.

Interestingly, high-sensitivity C-reactive protein wasn’t a predictor, suggesting systemic inflammation alone doesn’t capture the relevant pathophysiology and may be insufficient as a prevention target, said Scheltens.

One Medication, Multiple Pathways

Scheltens said the new analysis reinforces the concept that these common risk factors may contribute not only to cardiovascular disease but also to AD pathology. Obicetrapib has the potential to target these converging cardiovascular and neurodegenerative pathways with a single oral therapy, he added.

Unlike statins and most other lipid-lowering drugs, obicetrapib increases high-density lipoprotein (HDL) levels as well as lowers LDL levels. Scheltens said he believes the drug’s effect on p-tau217 is driven not only by lowering LDL but also by increasing HDL levels.

“HDL can cross the blood-brain barrier and remove cholesterol from neurons,” he said.

Unlike most other cholesterol-lowering drugs such as statins, obicetrapib increases HDL in addition to lowering LDL. “We think the effect on p-tau is not driven by just LDL lowering but by increasing HDL,” said Scheltens, who noted that “HDL can pass the blood-brain barrier and throw cholesterol out of the neurons.”

Scheltens also highlighted the drug’s “remarkable” safety profile as another potential advantage.

Yet another analysis presented at this year’s meeting suggested CETP inhibition influences multiple biological pathways implicated in AD, including amyloid processing, tau phosphorylation, neuroinflammation, neurodegeneration, and HDL function.

The findings support CETP inhibition as a potential upstream intervention targeting the lipid dysregulation thought to contribute to AD pathogenesis rather than focusing solely on downstream inflammation or amyloid clearance alone, the investigators noted.

These results have paved the way for a planned multisite trial of obicetrapib in high-risk APOE4 carriers.

Solid Rationale for a Prevention Trial

The finding that obicetrapib lowered p-tau217, particularly in APOE4 homozygotes, provides the rationale for the planned Alzheimer’s prevention trial, Jessica Langbaum, PhD, senior director of Alzheimer’s prevention and research at Banner Alzheimer’s Institute in Phoenix, told Medscape Medical News.

“Given that a sizeable proportion of older adults with high p-tau217 will go on to develop dementia over a 10-year period, an oral medication with minimal side effects that effectively lowers p-tau217 and has other health benefits. For example, lowering LDL and increasing HDL could meaningfully impact the burden of dementia and improve public health,” Langbaum said.

Scheltens reported being an employee of EQT Life Sciences, an emeritus professor at Amsterdam University Medical Center, and a consultant to NewAmsterdam Pharma. Langbaum reported no relevant disclosures.

https://www.medscape.com/viewarticle/lipid-lowering-med-heads-alzheimers-prevention-trial-apoe4-2026a1000ozo