Precision treatment for Alzheimer's disease reduces phosphorylated tau

Naveed Saleh, MD, MS | February 16, 2022

A new drug for Alzheimer's disease (AD) exhibited promising results, with biomarker reduction and memory enhancement after 6 months of treatment. 


Research scientist working in a lab

A number of recent clinical trials give hope for diseases ranging from breast cancer to Alzheimer disease.

The Phase 2 biomarker study for Alzheon’s ALZ-801 (265 mg twice daily) assessed change from baseline in plasma p-tau181 concentrations in 84 patients with early AD. The agent resulted in a 29% decrease in p-tau181 levels (p=0.028) at 26 weeks and an 18% reduction at 13 weeks (p=0.038), as well as dropping the plasma p-tau181/Aβ42 ratio by 30% at 26 weeks (p=0.022) and by 21% at 13 weeks (p=0.018). 

The study, explained

Patients in the study harbored either one or two copies of the ε4 allele of apolipoprotein E gene (ie APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively). Of note, the APOE4 genotype confers a manifold higher brain burden of neurotoxic amyloid oligomers and is the leading risk factor for the disease behind senescence. 

ALZ-801 is a disease-modifying treatment that inhibits the formation of neurotoxic soluble amyloid oligomers that mediate cognitive decline in Alzheimer's patients. The mechanism of action of this oral agent involves the inhibition of amyloid oligomers at the phase 3 clinical dose. It is safe and effective in patients with two copies of the apolipoprotein ε4 allele (APOE4/4), who are at highest risk with the disease.

A learning and memory test (ie, Rey Auditory Verbal Learning Test) was included as a secondary outcome. This test reflected improvements in immediate/delayed recall at week 26. 

“The several-fold greater reduction on p-tau181 biomarker compared to anti-amyloid antibodies provides further support for superior clinical benefit observed in Alzheon’s prior Alzheimer’s studies,” stated Martin Tolar, MD, PhD, Founder, President, and CEO of Alzheon in a press release. “Importantly, rather than slowing the cognitive decline of patients as seen in trials with other agents, subjects treated with ALZ-801 demonstrated significant cognitive gain from baseline status on memory tests, showing improvement over the course of treatment. These well-differentiated results position ALZ-801 to potentially become the first oral agent that can slow or even stop and prevent Alzheimer’s pathology in patients and healthy individuals at risk for the disease.”

Safety and tolerability

The safety profile of the agent is good with neither vasogenic edema nor drug-related adverse events experienced by the patients. Mild nausea was the most common negative side effect. Safety and tolerability aligned favorably with prior data from more than 2,000 AD patients contained in the proprietary safety database.

A phase 3 study of ALZ-801 is ongoing in APOE4/4 early AD patients, who represent about 15% of the AD population. The study assesses efficacy, safety, biomarker/imaging effects at the twice-daily 265 mg dose. This randomized controlled trial compares the oral agent with placebo for a study period of 78 weeks. The APOLLOE4 Phase 3 study with ALZ-801 is supported by a $47 million grant from the National Institute on Aging.

The phase 3 trial includes a robust array of biomarkers to determine clinical benefit, such as the gold-standard primary outcome ADAS-Cog 13 (Alzheimer’s Disease Assessment Scale-Cognitive Subscale), as well as p-tau181 in cerebrospinal fluid and blood, synaptic and inflammatory biomarkers, hippocampal volume, and cortical thickness measures. 

Plasma/CSF concentrations of phosphorylated tau (p-tau) are sensitive and specific markers of AD brain injury and neurodegeneration. This biomarker results from a reaction to toxic beta-amyloid (Aβ) oligomers. Levels of p-tau181 levels increase with AD progression and clinical deterioration. These levels can decrease with response clinically meaningful AD modifying treatments. 

According to Kaj Blennow, MD, PhD, a member of Alzheon’s Scientific Advisory Board and developer of the p-tau181 assay: 

“Alzheon has pioneered precision medicine in Alzheimer’s disease targeting neurotoxic amyloid oligomers, and now very promising biomarker data with ALZ-801 provide further support for this approach. Across many trials of anti-amyloid antibodies, p-tau181 has emerged as a consistent biomarker that correlates with amyloid reduction and clinical benefit. Upon analysis of the plasma p-tau181 data in our laboratory, we have observed an unprecedented reduction in this leading biomarker of Alzheimer’s pathology in patients taking ALZ-801 tablet for 6 months. This suggests a downstream effect on neuronal function and the potential for clinical efficacy of this novel treatment.”


  1. Alzheon Reports Industry-Leading Disease Modifying Effects from Phase 2 Biomarker Trial of Oral Tablet ALZ-801 (Valiltramiprosate) in Patients with Early Alzheimer’s Disease (press release). Alzheon.