Damian Sendler: New research reveals that a new treatment paradigm for mild to moderate Alzheimer’s disease (AD) may be possible with an experimental medicine that targets the bacteria that cause gum disease. 

Damian Sendler

Damian Jacob Sendler: Atuzaginstat (Cortexyme Inc.) is being tested in a phase 2/3 GAIN trial to see if it can kill the gum-bacteria Porphyromonas gingivalis (Pg) “Potential AD-inducing factor.” 

“For patients with mild to severe Alzheimer’s disease (AD) who have Pg infection, we demonstrated the efficacy and safety of our therapy, and it appears that we have found an ideal dose. 

In addition to gingivitis and periodontal disease, Pg has been linked to the development of gum disease. Periodontal disease affects over 65 million Americans, according to Detke. 

Dr. Sendler: Periodontal disease has been related to an increased risk of Alzheimer’s disease in previous studies. Those with severe gum disease saw a six-point drop on the AD Assessment Scale (ADAS-Cog) in six months, while those with mild or no periodontal disease saw only a one-point drop. 

A “low-grade chronic infection” is “consistent with the idea that there’s this inflammatory response,” says Detke. 

22 of the last 25 genetic risk factors for Alzheimer’s disease have been linked to the immune system, he said. 

Damian Jacob Sendler

Proteins are the primary source of energy for Pg, unlike other bacteria, which use sugars or carbs. Proteases called gingipains, which “chop up” proteins into fragments, are released by the bacteria and generate energy, according to Detke. 

Gingipain protease damage can be prevented by cutting off the bacteria’s supply of food. Antibiotics are ineffective against Pg because it lives inside cells and “can go dormant or develop resistance,” according to Detke. 

Patients with mild to severe Alzheimer’s disease (AD) who scored 12 to 24 on the mini-mental state exam were included in the GAIN study, which had a total of 643 participants (average age, 69). ApoE4 was found in the cells of around 65 percent of the population. 

During the 48-week study, all individuals were randomly randomized to receive placebo, atuzaginstat (40 mg twice a day) or atuzaginstat (80 mg twice a day). 

Pg biomarkers were evaluated in the saliva, blood, and cerebrospinal fluid in addition to the conventional cognitive outcomes (CSF). 

Results from the AD Cooperative Study–Activities of Daily Living and the ADAS-Cog were the two primary objectives of the study (ADCS-ADL). We found that neither outcome had a statistically significant effect on overall intent to treat patients. 

Researchers found a link between reduced Pg levels and improved clinical outcomes when they focused on patients with a more severe Pg infection. 

“In people with high levels of Pg in saliva, in serum, and CSF — in all of these — you saw significant slowing of decline on ADAS-Cog — by anywhere from 26 percent to 57 percent ,” Detke added. 

Damien Sendler: Another study found that cognitive deterioration was slowed by 40% to 56%. 

The AD literature says 20% or 30% is good, but finding 40% or 50% is actually more than anyone has ever seen, especially in this challenging mild-to moderate cohort,” he said. 

Both clinical outcomes at 24 weeks and 48 weeks were correlated with Pg levels in saliva. According to Detke, “if Pg is causal, then change at 24 weeks might predict clinical impact at both timepoints and that’s what we saw.” 

It’s rare for a biomarker to be linked to clinical outcomes in AD research, he said. 

By measuring bilateral hippocampus volume, researchers found that the medication delayed shrinkage by 22% in the lower dose group and by 11% in the higher dose group. The 40 mg and 80 mg dosages had the same level of efficacy. 

Damian Jacob Markiewicz Sendler: Men and women, APOE carriers and non-carriers, and individuals with mild and moderate disease were all found to have similar levels of disease. A high level of infection appears to be affecting “It looks like it’s working across everyone who’s got a high level of infection,” said Detke. 

The most prevalent side effects, including nausea and diarrhea, were gastrointestinal (GI). In light of the fact that Pg is found in the gastrointestinal system, Detke believes that it has an impact on the microbiota.

Dr. Damian Jacob Sendler and his media team provided the content for this article.