Experimental Med May Slow Alzheimer’s Biomarker Progression

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.