Written by Corrie Pelc — Fact checked by Amanda Ward
One gene variant that is particularly associated with Alzheimer’s disease risk is APOE4. Researchers estimate that between 15-25% of the general public have the APOE4 gene variant.
And some people carry two copies of the gene called APOE4/4that increases their Alzheimer’s disease risk even further. Previous research reports that people who have two copies of the APOE4 gene variant may increase their risk of developing Alzheimer’s disease by age 85 by as much as 60%.
“APOE4/4 patients, who represent about 15% of all Alzheimer’s disease cases, face the highest genetic risk, experience faster disease progression, and have the fewest treatment options,” Susan Abushakra, MD, a board certified neurologist and chief medical officer of biopharmaceutical company Alzheon, told Medical News Today. “APOE4/4 Alzheimer’s disease patients face the highest risk of brain edema/swelling and brain bleeds (called ARIA-E and ARIA-H) with the current anti-amyloid immunotherapies.”
According to Abushakra, valiltramiprosate is the first investigational oral therapy developed for genetically at-risk APOE4/4 patients.
“One of the first abnormalities in the Alzheimer’s disease brain is the clumping (aggregation) of small proteins called amyloid into harmful (neurotoxic) clusters called oligomers that clump further into larger insoluble amyloid plaques,” she explained.
“ALZ-801 is designed to work early in this process to block the formation of these neurotoxic soluble amyloid oligomers, thereby protecting neurons from their toxic effects,” she said.
How this medication is different
“Unlike antibody infusions that remove plaques later in the disease, ALZ-801 works earlier, before plaques form, aiming to slow or stop disease progression and avoid the ARIA side effects seen with other treatments. The APOLLOE4 study is the first Phase 3 trial conducted entirely in people with two APOE4 genes, the group at highest genetic risk for Alzheimer’s.”
— Susan Abushakra, MD
For this study, researchers recruited 325 study participants between the ages of 50-80 years old with APOE4/4 and at the early symptomatic stages of Alzheimer’s disease, including MCI and mild Alzheimer’s disease dementia. Participants were randomly placed into two groups, once receiving valiltramiprosate and the other given a placebo.
At the study’s conclusion, researchers found that APOE4/4 study participants with MCI that were treated with the investigational drug experienced a slow-down in brain atrophy over multiple brain regions, as well as reduced water diffusivity, which is seen in the slowing of neurodegeneration.
“In a prespecified analysis at the MCI stage, which is the earliest symptomatic phase of Alzheimer’s, we saw signals of clinically meaningful cognitive and functional benefits, along with protection against brain atrophy,” Abushakra said. “Patients who received ALZ-801 over 78 weeks had larger brain volumes on MRI than those on placebo.”
“We used another imaging technique called diffusion MRI, that measures water movement and content in brain tissue,” she continued. “Using this imaging technique, ALZ-801 treated patients had less water in their brain than those on placebo. The relatively larger brain volume on ALZ-801 was not from larger water content, but from preservation of neurons and brain tissue. This suggests that in MCI patients, ALZ-801 can slow neurodegeneration and that leads to clinical benefits.”
In the official press release, researchers stated they were unable to achieve the primary clinical outcome of this study. When asked about this, Abushakra explained that, “The topline results earlier this year noted the study didn’t meet its main endpoint in the overall early Alzheimer’s population. However, this new peer-reviewed publication provides a deeper look at a prespecified analysis by disease stage.”
“Alzheimer’s is a complex, multi-stage disease, and outcomes depend on when treatment begins,” she explained. “In this study, patients who were already at the mild dementia stage did not show meaningful clinical benefits, but patients treated early at the MCI stage saw the greatest benefit. The MCI patients showed meaningful slowing of memory loss, stabilization of function, and significant protection from brain shrinkage/atrophy.”
“The results underscore a clear message: timing and patient selection are key — and early diagnosis and intervention make the biggest difference. We plan to build on the learnings in future trial designs as we continue clinical development and regulatory discussions to bring ALZ-801 to patients as quickly as possible.”
— Susan Abushakra, MD
MNT had the opportunity to speak with Jasdeep S. Hundal, PsyD, ABPP-CN, director of The Center for Memory & Healthy Aging at the Hackensack Meridian Neuroscience Institute at Jersey Shore University Medical Center, and associate professor of psychiatry neurology at Hackensack Meridian Health School of Medicine in New Jersey, about this study, who commented his first reaction to its findings was one of cautious optimism.
“While the treatment does not show clear benefits for all early Alzheimer’s patients, it did show promising results in those with very early symptoms who meet criteria for MCI. These patients experienced slower memory decline and less brain shrinkage.”
— Jasdeep S. Hundal, PsyD, ABPP-CN
“Most importantly, the drug appeared to be safe, especially compared to other Alzheimer’s treatments that carry serious side effects in this high-risk group,” he continued. “If future studies confirm these findings, this could become a safer, easier-to-use option for patients who currently have very limited choices.”
MNT also spoke with Clifford Segil, DO, neurologist at Providence Saint John’s Health Center in Santa Monica, CA, about this research.
“I agree with the researchers that we still need to find medications for memory loss that are safe, have efficacy, are accessible, and can provide clinically meaningful results,” Segil commented.
“Medications being used now for weight loss provided visible and clear results, and amyloid medications being used now in addition to mainstay oral medications for memory loss like Aricept/Namenda, do not show visible meaningful improvements in patients memories and cognition. We need to find medications which work better than current anti-amyloid therapies and mainstay oral medications which affect brain acetylcholine and NMDA levels,” he told MNT.
“Unfortunately, this oral anti-amyloid medication did not translate into any meaningful cognitive benefits even though its use resulted in decreasing certain brain regions volume or hippocampal atrophy, as there was no clinical improvement with this oral anti-amyloid medication (that) showed only nominal significant positive clinical effect in the MCI group.” — Clifford Segil, DO
“I think the same modern imaging techniques used in the study should be applied to patients with Alzheimer’s dementia who currently are receiving Aricept or Namenda to see if these medications, which are FDA approved for dementia, also provide the same anatomical benefits as these oral amyloid medications,” Segil added.
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