A promising new oral treatment for Alzheimer’s disease, designed specifically for people with a high-risk APOE4 gene variant, has shown encouraging results in a phase 3 clinical trial. The investigational pill, called valiltramiprosate (ALZ-801), may help slow brain atrophy and neurodegeneration in patients with early-stage Alzheimer’s, particularly those with mild cognitive impairment (MCI).
The study, published in the journal Drugs, was conducted by biopharmaceutical company Alzheon, led by Dr Susan Abushakra, Chief Medical Officer and board-certified neurologist.
Understanding the genetic risk
The APOE4 gene variant is one of the most significant genetic risk factors for Alzheimer’s disease. About 15–25% of the global population carries at least one copy of APOE4, while individuals with two copies (APOE4/4) face up to a 60% increased risk of developing Alzheimer’s by age 85.
Dr Abushakra explained that APOE4/4 patients, who represent nearly 15% of all Alzheimer’s cases, experience faster disease progression and fewer treatment options. They are also at higher risk of developing ARIA-related brain swelling and bleeding associated with current anti-amyloid antibody infusions.
How valiltramiprosate (ALZ-801) works
Valiltramiprosate is the first oral therapy developed specifically for genetically high-risk APOE4/4 individuals. It works by blocking the early aggregation of amyloid proteins in the brain — the initial step in Alzheimer’s disease progression.
“ALZ-801 works earlier than antibody infusions — before amyloid plaques form,” said Dr Abushakra. “It aims to slow or stop disease progression while avoiding the side effects seen with current treatments.”
Unlike existing anti-amyloid immunotherapies that remove plaques later in the disease, ALZ-801 targets neurotoxic amyloid oligomers before they cluster, potentially preserving brain tissue and neuron function.
Study design and key findings
The phase 3 APOLLOE4 trial enrolled 325 participants aged 50–80 with APOE4/4 genotype and early Alzheimer’s disease, including those with mild cognitive impairment (MCI) and mild dementia. Participants were randomly assigned to receive either valiltramiprosate or a placebo.
At 78 weeks, researchers observed that patients with MCI who received ALZ-801:
- Showed slower brain atrophy across multiple regions
- Maintained larger brain volumes on MRI compared to placebo
- Experienced reduced water diffusivity, a marker of slower neurodegeneration
“These imaging findings suggest ALZ-801 can preserve neurons and brain tissue in early Alzheimer’s patients,” said Dr Abushakra. “The treatment showed signals of meaningful cognitive and functional benefit at the MCI stage.”
Why early intervention matters
Although the study did not meet its primary endpoint across the entire early Alzheimer’s group, the results were strongest among those treated earlier in the disease course.
“Timing and patient selection are key,” Dr Abushakra explained. “Patients treated at the mild dementia stage showed limited benefit, but those treated early — at the MCI stage — experienced measurable improvements in cognition and brain preservation.”
The team plans to build on these findings in future clinical trials, emphasizing the need for early diagnosis and intervention in genetically high-risk individuals.
Expert opinions: cautious optimism
Dr Jasdeep S. Hundal, Director of The Center for Memory & Healthy Aging, called the findings “cautiously optimistic.”
“While the treatment did not show clear benefits for all early Alzheimer’s patients, those at the MCI stage showed slower memory decline and less brain shrinkage,” he said. “Importantly, ALZ-801 appeared safe, especially compared to current therapies that carry higher risks.”
Dr Clifford Segil, Neurologist at Providence Saint John’s Health Center, emphasized the ongoing need for safe and accessible Alzheimer’s treatments.
“We still need oral medications that are safe, effective, and show meaningful improvements in cognition,” Dr Segil noted. “This study is a step in that direction, though more long-term data are needed.”
What this means for Alzheimer’s care
The potential of ALZ-801 as a safer, easier-to-administer oral option could mark a major advancement for patients who currently have limited therapeutic choices. If future trials confirm its benefits, ALZ-801 could become the first gene-targeted pill to slow disease progression in high-risk Alzheimer’s patients.
