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TORONTO — The experimental drug obicetrapib, a potent oral cholesteryl ester transfer protein (CETP) inhibitor, significantly slowed Alzheimer’s disease (AD) biomarker progression over 12 months in patients with cardiovascular disease, new research showed.

Results revealed the drug led to a 20% improvement in levels of phosphorylated tau 217 (p-tau217) — an important indicator of AD pathology — in patients carrying the apolipoprotein E (APOE4) allele. About 65% of people with AD are APOE4 carriers.

The treatment was already shown to reduce LDL cholesterol and increase HDL cholesterol in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH).

It’s encouraging to have a drug that treats cardiovascular disease and treats or prevents AD, study investigator Philip Scheltens, MD, PhD, professor of neurology and founder of the Alzheimer’s Center, Amsterdam University Medical Center, Amsterdam, the Netherlands, told Medscape Medical News.

“The study shows that AD and CVD are closely related, especially with increasing age, and one of the linking pins is APOE4. Lowering LDL cholesterol and mostly increasing HDL cholesterol with obicetrapib seems to have a beneficial effect on AD pathology as measured by the biomarkers,” Scheltens said.

The findings were presented July 30 at the Alzheimer’s Association International Conference (AAIC) 2025.

Targeting LDL 

Disrupted cholesterol metabolism plays a central role in the biology of AD with APOE status serving as a critical link between lipid dysregulation and AD. The Lancet Commission recently identified high LDL cholesterol as a dementia risk factor.

APOE4, which raises LDL cholesterol and lowers HDL cholesterol, is a powerful genetic factor in the biology of AD. It was recognized as a cardiovascular disease risk factor before being identified as a risk factor for AD.

Carriers of APOE4 face a higher risk of side effects from current anti-amyloid antibodies, including an increased likelihood of brain bleeding and swelling — known as amyloid-related imaging abnormalities (ARIA).

The researchers drew on the randomized, blinded BROADWAY trial, which examined the effect of 12 months of 10 mg obicetrapib or placebo — added to maximally tolerated lipid-modifying therapy — on lipid levels in patients with ASCVD or HeFH.

Because statin therapy alone had not sufficiently reduced cholesterol in these patients, obicetrapib was incorporated into their treatment regimen. Results showed obicetrapib reduced LDL cholesterol by 33% compared to placebo (P <.0001) and increased HDL cholesterol, at day 84, in patients with ASCVD or HeFH. 

For the current study, researchers analyzed AD biomarkers measured at baseline and again at 12 months. The analysis included 1515 participants aged 66-70 years; 32.9% were female, 84.6% were White, and 21.3% carried the APOE4 genotype. As is typical in a cardiovascular population, participants had relatively high rates of diabetes (37.8%) and hypertension (84.7%).

Novel Finding?

The study’s primary outcome was the change in p-tau217, a biomarker considered one of the most sensitive indicators of Alzheimer’s disease pathology, with levels typically rising before symptoms appear.

Other biomarkers of interest included p-tau181, amyloid-beta (Aβ) 42/40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL). An exploratory outcome was the ratio of p-tau217 to Aβ 42/40.

The mean percentage change in p-tau217 was 1.99 in the obicetrapib group compared with 4.98 in the placebo group (P = .0188).

Other mean percentage changes were: 

• -1.20 in the obicetrapib group vs -2.03 in the placebo group (P = .57) for NFL
• 1.48 vs 3.40 (P = .07) for GFAP
• 1.27 vs 1.68 (P = .76) for p-tau181
• -0.44 vs 1.03 (P = .29) for Aβ 42/40

For the p-tau217 to Aβ 42/40 ratio, the mean percentage change was 2.51% in the obicetrapib group vs 6.55% in the placebo group (P = .0042).

Among E4/E4 carriers (homozygotes), the mean percentage change in p-tau217 was -7.81% in the treated group vs 12.67% in the placebo group, resulting in a between-group difference of -20.48% (P = .010), although this subgroup included only 29 participants. E4 carriers receiving treatment also showed greater improvements than those on placebo in NFL, GFAP, and p-tau181.

Findings like these have never been shown before, Scheltens noted, while acknowledging that it’s still early days. “Keep in mind, regular statin therapy has never demonstrated any effect in Alzheimer’s disease,” he said. 

Obicetrapib was well tolerated, with frequency and severity of adverse events being similar to placebo. Adverse events were seen in 60.8% of participants in the placebo group and 59.7% in the obicetrapib group.

Replication in a cohort of individuals with mild cognitive impairment due to AD, including cognitive and functional assessments, “appears to be the next step,” in the research, said Scheltens.

Missing Details

Commenting for Medscape Medical News, David Knopman, MD, a neurologist at the Mayo Clinic in Rochester, Minnesota, whose research focuses on late-life cognitive disorders, noted that both the baseline cognitive status of study participants and the cholesterol criteria for enrollment remain unclear. 

“There are too many missing details about the original protocol, including prespecified outcomes and inclusion criteria,” he said.

The investigators’ main claim is that because obicetrapib lowered plasma p-tau217, the drug might have some value in AD, said Knopman. 

“A small movement in p-tau217 in this group of patients with cardiovascular disease is interesting, but hard to interpret because the fluctuations in the plasma levels of p-tau217 were likely operating in the nondiagnostic noise range of the assay,” he noted.

The finding that p-tau217 was reduced by more than 20% among E4 homozygotes is an “inappropriate cherry-picked claim,” said Knopman. He noted that this subgroup of 29 participants represented only 2% of the study population, and across the full study cohort of 1515 participants, the decline in p-tau217 was just 2.99%. 

However, he noted, the new results could form the basis for proceeding to a phase 3 study in which cognitive outcomes and amyloid PET measurements are used as primary outcomes.

Scheltens is a full-time employee of EQT Life Sciences, emeritus professor at Amsterdam University Medical Center, and consultant to New Amsterdam Pharma. Knopman reports no relevant financial relationships.

Adolescents who undergo bariatric surgery face a higher risk of weight regain, which can undermine treatment success and long-term health, if they have elevated blood levels of per- and polyfluoroalkyl substances (PFAS) prior to the procedure, according to new USC research. PFAS are manufactured chemicals used in consumer products that accumulate in the body over time and are increasingly linked to a range of health concerns, including kidney problems, liver damage and various cancers. The findings were just published in the journal Obesity.

Bariatric surgery, a form of weight-loss surgery that alters the digestive system, is an effective treatment for severe obesity that can reduce the risk of long-term health problems such as type 2 diabetes and cardiovascular disease. But many people who get bariatric surgery regain significant weight over time, which can limit the procedure’s long-term health benefits. Researchers believe PFAS exposure may play a role in weight regain because the chemicals are known to disrupt endocrine and metabolic processes.

“With the growing use of weight loss interventions around the world, it’s critical for us to understand the association between PFAS and successful weight loss management, including what this means for long-term outcomes,” said Brittney Baumert, PhD, MPH, a postdoctoral research fellow in population and public health sciences at the Keck School of Medicine of USC and the study’s first author.

With funding from NIH, Baumert and her colleagues conducted the first long-term study linking PFAS exposure to bariatric surgery outcomes in teens. They tracked 186 adolescents for five years, finding that those with higher PFAS blood levels before surgery regained more weight and had greater increases in waist circumference than those with lower PFAS levels. The strongest associations were observed in a class of PFAS known as sulfonic acids, which includes perfluoroctaansulfonaten (PFOS), perfluorohexane sulfonic acid (PFHxS) and perfluoroheptanesulfonic acid (PFHpS).

The findings could help health care providers tailor treatment plans to better serve patients, as well as offer hints about the biological mechanisms that underlie the health effects of PFAS. The study also underscores the need for stronger limits on PFAS levels in food packaging, water supplies and other sources of exposure, the researchers said.

“Our study shows a clear association between PFAS exposure and weight-related outcomes in bariatric surgery for adolescents,” Baumert said. “PFAS are a modifiable risk, which is why protective policies are so important to reduce exposure and safeguard public health—especially for vulnerable populations.”

Tracking long-term outcomes

The researchers analyzed data on 186 teens from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study who underwent bariatric surgery between 2007 and 2012. Before surgery, blood samples were collected from each patient and tested for levels of seven types of PFAS. Weight, body mass index (BMI) and waist circumference were measured before surgery and six months, one year, three years and five years after surgery.

To analyze the data, the researchers divided patients into three groups based on their blood PFAS concentrations: low, medium and high exposure.

Overall, patients with higher blood levels of PFOS, PFHxS and PFHpS gained more weight and had greater increases in waist circumference one to five years post-surgery, compared to patients with lower blood levels of those chemicals.

To illustrate the difference for PFOS, adolescents with a starting body weight of 328 pounds in the low exposure group regained, on average, 35.9 pounds by the five-year mark. But teens of the same weight with the highest PFOS exposure regained, on average, 46.9 pounds.

For PFHpS, teens in the highest exposure group regained weight at an average of 4.3% of their baseline bodyweight per year, compared to 2.7% per year in the lowest exposure group.

Better patient care

The study adds to the mounting evidence supporting stronger regulation of PFAS, the researchers said—particularly in public water supplies, which are the greatest source of exposure.

It also points to potential strategies for improving patient care. Bariatric surgery is costly and invasive, so understanding who is likely to benefit can help providers make informed decisions about the best course of treatment for each individual.

“We’re also interested in exploring whether PFAS exposure is relevant to other weight loss interventions,” including GLP-1 medictions such as Ozempic, Baumert said.

In addition, Baumert and her team are investigating the link between PFAS and long-term metabolic health. For example: How might PFAS exposure relate to a person’s risk for type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD)? The researchers are now analyzing those connections using data from the Teen-LABS study. 

Reference: Baumert BO, Costello E, Li Z, et al. PFAS exposure and postoperative weight regain in adolescents after bariatric surgery: findings from the teen-labs study. Obesity. 2025;n/a(n/a). doi: 10.1002/oby.70009

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