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4-year Alzheimer's trial data just dropped - 69% of early-stage patients showed zero decline

and there's finally good news for APOE4 carriers

T
· Reviewed by Dr. Kevin Tran, PharmD

Key takeaways · TL;DR

Breakthrough AAIC 2025 data: Lecanemab 4-year Yale extension showed 56 percent reduced dementia progression and 69 percent of low-tau patients had zero decline. Donanemab benefits doubled over 3 years and starting 18 months earlier gave 27 percent better outcomes. Obicetrapib, an oral CETP inhibitor, reduced plasma pTau-217 by 20 percent in APOE4/E4 carriers.

Definition

A drug class that blocks cholesteryl ester transfer protein. Originally developed for cardiovascular disease to raise HDL.

Definition

Clinical Dementia Rating Sum of Boxes. A scale measuring cognitive and functional decline in Alzheimer disease.

AAIC 2025 Long-Term Alzheimer Drug Data

DrugDurationKey APOE4 Finding
Lecanemab4 years56% reduced dementia progression; 69% zero decline in low-tau
Donanemab3 yearsBenefit doubled to 1.2 CDR-SB; earlier start = 27% better
ObicetrapibCross-sectional20% pTau-217 reduction in APOE4/E4 carriers

In this video, I analyze recent clinical trial findings that highlight what’s on the horizon for innovative therapies targeting APOE4 carriers and Alzheimer’s disease.

The game-changing findings:

Lecanemab (4-year data from Yale):

  • 56% reduction in progression to dementia

  • 69% of low-tau patients had ZERO decline after 4 years

  • Safety update: 92% of ARIA happens in first 6 months, then drops to placebo levels

Donanemab (3-year data from Eli Lilly):

  • Benefits DOUBLED over time (0.6 to 1.2 CDR-SB points)

  • Starting 18 months earlier = 27% better outcomes

  • This suggests actual disease modification, not just temporary slowing

Obicetrapib (surprise finding from Amsterdam):

  • It's an oral cholesterol drug (CETP inhibitor)

  • APOE4/4 carriers showed 20% reduction in P-tau217

  • First oral medication showing specific benefit for E4 carriers

Reality check:
These drugs slow decline, they don't reverse existing damage. But the fact that benefits keep growing over 4 years (instead of plateauing) is huge. It suggests we're actually changing the disease trajectory.

The critical message:
If you're at risk, get tested early. The difference between starting treatment immediately vs waiting 18 months is massive.

If you are an APOE4 carriers, join us in The Phoenix Community and take action TODAY

The insights are summarized from the July 2025 Alzheimer’s Association International Conference session, Developing Topics on Innovative Therapeutic Approaches.

I do not have any affiliation with any of the companies mentioned in this video. I am an APOE4/4 carriers looking for solutions myself and sharing what I learn along the way in the Phoenix Community and occasionally with other groups.

Sources:
The insights are summarized from the July 2025 Alzheimer’s Association International Conference session, Developing Topics on Innovative Therapeutic Approaches.

Researchers in this session:
John R. Sims (Eli Lilly and Company, IN, USA) - Donanemab in Early Symptomatic Alzheimer's Disease: Efficacy and Safety from the TRAILBLAZER‐ALZ 2 Long-Term Extension

Christopher H van Dyck (Yale School of Medicine, CT, USA; Alzheimer's Disease Research Unit, Yale School of Medicine, CT, USA) - The Lecanemab Clarity AD Open-Label Extension in Early Alzheimer’s Disease: Initial Findings From the 48-Month Analysis

Hui-dong Tang (Department of Geriatrics, Medical Center on Aging of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China) - Microglial Activation Correlates with Amyloid Clearance and Cognitive Benefit in Lecanemab-Treated Early AD Patients

Philip Scheltens (Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Netherlands) - Effects of Obicetrapib, a Potent Oral CETP Inhibitor, on Alzheimer's Disease Biomarkers in 1727 Patients with cardiovascular disease

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FAQ

Frequently asked questions.

What did the 4-year lecanemab trial data show?
The Clarity AD Open-Label Extension 48-month analysis from Yale, presented by Dr. Christopher van Dyck at AAIC 2025, showed lecanemab reduced progression to dementia by 56 percent over 4 years. Remarkably, 69 percent of low-tau early-stage patients had zero cognitive decline after 4 years of treatment. The safety profile also improved dramatically: 92 percent of ARIA events happened in the first 6 months, then dropped to placebo levels, meaning long-term lecanemab use is safer than initial trial data suggested once past the early window.
What did the 3-year donanemab trial data show?
The TRAILBLAZER-ALZ 2 long-term extension from Eli Lilly, presented by John Sims, showed donanemab benefits doubled over time from 0.6 to 1.2 CDR-SB points between years 1 and 3. Starting treatment 18 months earlier produced 27 percent better outcomes than delayed treatment. The growing rather than plateauing benefit strongly suggests donanemab is actually modifying disease trajectory rather than temporarily slowing decline. This changes how clinicians should think about early intervention timing.
What is obicetrapib and why is it exciting for APOE4 carriers?
Obicetrapib is an oral CETP inhibitor originally developed as a cardiovascular cholesterol drug. In a study of 1727 patients with cardiovascular disease presented by Philip Scheltens from Amsterdam, APOE4/E4 carriers showed a 20 percent reduction in plasma pTau-217, an Alzheimer biomarker. This is the first oral medication to show specific Alzheimer-relevant biomarker benefit for E4 homozygotes. Because it is taken as a pill and already has a cardiovascular safety profile, it represents a potentially accessible alternative to monthly antibody infusions if benefits are confirmed.
Why does starting Alzheimer treatment earlier make such a big difference?
The donanemab 3-year data showed that patients who started treatment 18 months earlier had 27 percent better outcomes than those who waited. The lecanemab data showed that 69 percent of low-tau patients, those with minimal existing pathology, had zero decline over 4 years. The pattern is clear: these drugs slow decline but cannot reverse existing damage, so the earlier you start, the less damage there is to manage. For APOE4 carriers, this argues strongly for early testing, early biomarker monitoring, and early access to treatment when warranted.
Do lecanemab and donanemab actually modify Alzheimer disease?
The growing evidence points toward yes. Historically these drugs were described as slowing decline by a modest amount, which critics called temporary symptomatic relief. But the 4-year lecanemab and 3-year donanemab extension data show benefits that grow over time rather than plateauing. If the drugs only provided temporary relief, the gap between treatment and placebo would stabilize. Instead, the gap widens, which is the signature of actual disease modification. This is a significant change in how the therapeutic class is understood.
What is ARIA and how common is it with lecanemab?
ARIA, short for amyloid-related imaging abnormalities, includes ARIA-E (brain swelling) and ARIA-H (brain bleeding) caused by amyloid antibody therapies. With lecanemab, 92 percent of ARIA events happen in the first 6 months of treatment, after which the rate drops to placebo levels. This front-loaded risk profile means MRI monitoring is most important early, and patients who tolerate the first 6 months face dramatically lower ongoing risk. APOE4/E4 carriers still face the highest ARIA risk and require careful risk-benefit discussion before starting.
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