A cholesterol pill is now being tested as a way to slow Alzheimer’s disease before any symptoms appear. NewAmsterdam Pharma has dosed the first participant in SPINOZA, a trial of its drug obicetrapib in adults whose tests show early signs of Alzheimer’s disease but who have no noticeable memory or day-to-day problems yet1. The trial is what researchers call a Phase 2b study, a mid-sized test meant to show whether a drug is worth a larger, final trial2.
Most Alzheimer’s drug programs target amyloid or tau, the two proteins that build up in the brain, in people who already have symptoms1. This trial goes earlier, and it uses a drug built for the heart rather than the brain1.
What the trial will test
The registry record lists a planned 400 participants aged 55 to 85, split into two groups: one takes 10 mg of obicetrapib once a day, the other takes matching dummy tablets (placebo)3. People are assigned by chance, and the trial is “triple blind”: participants, their care providers and the investigators do not know who gets which pill4.
Entry depends on genes. People whose APOE gene type does not meet the trial’s rules are excluded3. APOE4, one version of this gene, is the main known genetic risk factor for Alzheimer’s5. The public record does not spell out exactly which gene types qualify.
The main measure is the change in p-tau217 from the start to week 522. P-tau217 is a blood marker that climbs as amyloid and tau build up, and it is now one of the better blood tests for Alzheimer’s changes in the brain5. Other measures include further blood markers, such as the ratio of two forms of amyloid, and a set of memory and thinking tests called PACC54.
The trial began in September 20262. As of late September it listed one site, K2 Medical Research in Nashville, Tennessee4. Main data collection is due to finish in September 2028, and the full study in May 20294.
The evidence so far
Obicetrapib blocks a protein called CETP, which moves cholesterol out of HDL (“good” cholesterol) particles and into LDL (“bad” cholesterol) and other particles that end up in artery walls5. Blocking it lowers LDL and raises HDL5. The European Commission has approved it for lowering cholesterol, sold as Ubeslo on its own and as Evlarco combined with ezetimibe5. In the main trial behind that approval, called BROADWAY, LDL fell 29.9% after 12 weeks on the drug, against a 2.7% rise on placebo, in 2,530 high-risk patients5.
The Alzheimer’s idea rests on three lines of earlier work:
- Genes. In a group of older adults, people with two copies of a gene variant that lowers CETP activity had slower memory decline and less dementia, and later work suggests the effect is strongest in people who also carry APOE45. This is an association, not proof that the drug would do the same.
- A small early study. In 2023 the company reported results from 13 people with early Alzheimer’s who carried at least one APOE4 copy and took the drug for 24 weeks, with no comparison group6. It reported drops of 11% and 12% in two cholesterol by-products in the fluid around the brain and spine, an 8% rise in a blood amyloid ratio, stable levels of another tau marker, and no serious side effects6.
- A side analysis of the heart trial. BROADWAY stored blood samples, and a planned analysis measured Alzheimer’s markers in 1,535 of its 2,530 participants, none of whom had a dementia diagnosis5. Over the year, p-tau217 rose 4.94% on placebo5 and rose less on obicetrapib7. The difference looked stronger in APOE4 carriers and strongest in people with two APOE4 copies, where p-tau217 fell on the drug7.
What it does not show yet
SPINOZA has no results. Even when it reports, its main measure is a blood marker, not whether people develop memory loss or dementia2.
The earlier hints have clear limits. The 13-person study had no placebo group6. In the heart trial’s analysis, only 29 people had two APOE4 copies, the group with the most striking result7. Hussein Yassine, who wrote about the finding, noted that the Alzheimer’s analysis was planned in advance but still sat inside a trial built to answer a heart question, and that such a signal “does not, by itself, prove Alzheimer’s prevention, clinical benefit, or disease modification”7. He added that the possible ways a blood cholesterol drug could affect the brain are plausible but not proven7.
Testing people without symptoms is hard. The Clinical Trial Vanguard pointed out that showing an effect before decline starts needs either very sensitive markers, a very long follow-up, or both, and that the link between blocking CETP and brain disease “is not settled”1.
On safety, the drug class has a troubled past. Four earlier CETP blockers failed to reach patients; the first, torcetrapib, increased deaths and heart events5. In BROADWAY, 229 patients who wore 24-hour monitors showed no change in blood pressure, yet the European regulator’s summary lists high blood pressure among the drug’s most common side effects5. It has also not yet been shown that the drug prevents heart attacks or strokes; a trial of 9,541 people called PREVAIL is meant to answer that5.
Who is behind it
NewAmsterdam Pharma sponsors and pays for SPINOZA3. The company is based in Naarden, the Netherlands, and Miami, and is listed on Nasdaq6. It runs several other trials of the same pill, including a cholesterol study in people with type 2 diabetes or metabolic syndrome8.
Its leaders have spoken hopefully about the Alzheimer’s work. After the 2023 results, chief executive Michael Davidson said the company believed the drug “could offer a meaningful advancement for a high-risk patient population”6. Jeffrey Cummings, a brain researcher at the University of Nevada, Las Vegas, quoted in the same company release, said:
“Approximately two thirds of patients with Alzheimer’s dementia carry at least one copy of the ApoE4 gene and CETP loss-of-function mutations have been shown to protect against ApoE4-associated AD risk.”
That statement appeared in a company announcement6. The commentaries by Paddy Barrett, a doctor writing on Substack, and by Yassine are independent analyses, not company material57.
How it fits the field
Approved Alzheimer’s drugs such as lecanemab work by clearing amyloid in people who already have symptoms, and SPINOZA aims further upstream1. Lecanemab itself is also being tested earlier, in a trial called AHEAD 3-45 with about 1,400 people with preclinical Alzheimer’s4. Obicetrapib’s approach is different: it targets cholesterol handling rather than clearing plaques1. Interest in using existing drugs to prevent Alzheimer’s is growing, as in a US-funded effort to test existing drugs for prevention, and in studies focused on APOE4 carriers such as a recent transplant-drug study.
What to watch next
The first thing to watch is enrollment: how fast SPINOZA reaches 400 people, and whether more sites open beyond Nashville4. The Clinical Trial Vanguard suggested the key number when data arrive will be how the blood marker changes, since that will decide whether a larger prevention trial makes sense1. Results on the heart side, from PREVAIL, will also shape how the drug is seen5. Biohack will update this thread as the trial moves forward.
