Microbiome Manipulation with Oligomannate for Dementia

In 2020 a remarkable case report was published entitled “Rapid improvement in Alzheimer’s disease symptoms following fecal microbiota transplantation: a case report.” The FDA allows the use of fecal transplants for the treatment of recalcitrant infections of a bad bug known as C diff. Serendipitous improvements following such transplants across a range of conditions have been reported, including autism, baldness, and multiple sclerosis.

The dementia report involved an 82-year-old man with a five-year history of gradually declining memory and cognition. His Mini-Mental State Examination score was 20 (out of 30), indicating mild cognitive impairment. But two months after receiving a fecal transplant from his wife his score was 26, which is considered normal cognition. By month six post-transplant, the patient achieved a near perfect score of 29, and he also reported a marked improvement in mood, social interaction, and expressiveness.

The potential role of gut flora in Alzheimer’s is not completely out of left field. Butyrate, which is what our good gut bugs produce when we eat fiber, is absorbed from our colon into our bloodstream and can cross the blood-brain barrier and improve the memory function of mice and rats. In people, the microbiomes of Alzheimer’s patients have been found to have fewer good bugs—butyrate-producing bugs—and more bad bugs—pro-inflammatory bugs. One reason this isn’t just dismissed as a simple consequence of poorer (lower fiber) diets is that mice transplanted with stool from an Alzheimer’s patient perform significantly worse on cognitive tasks than those fed fecal samples from a non-demented individual. Could it be that fecal transplants actually help? We’ll find out soon, as a randomized, double-blind, placebo-controlled trial of fecal transplants for Alzheimer’s disease is currently underway.

There have been about two dozen studies of prebiotics, probiotics, and fermented foods for cognition. Most reported improvements in certain specific tasks, but the findings were inconsistent such that, overall, there was no significant improvement in global cognition, nor in any single cognitive domain. Of course, differences in dosing and formulations make it hard to draw conclusions from such heterogenous data points. There was a randomized double-blind placebo-controlled trial published that purported to show a significant improvement in Mini-Mental State Exam scores, but the validity of the data was later called into question. Similar concerns haunt oligomannate, a prebiotic conditionally approved to treat mild-to-moderate Alzheimer’s disease in China in 2019.

Traditional Japanese eating patterns have been associated with better cognitive function in the elderly and lower risk of dementia. That was evidently the inspiration to try oligomannate, a prebiotic derived from a type of brown seaweed, on a mouse model of Alzheimer’s disease. Cognition improved in the mice, but a subsequent 24-week human trial in Alzheimer’s patients failed to offer a significant benefit. Not to be discouraged, the Shanghai Green Valley Pharmaceutical Company, the developers of oligomannate, funded another human trial, a 36-week multicenter, randomized, double-blind, placebo-controlled trial of more than 800 patients with mild-to-moderate Alzheimer’s dementia. Significant improvements in cognition were noted starting within four weeks in those randomized to oligomannate compared to placebo. Based on that trial, it went on sale in China in December 2019 for about $500 a month.

Currently, oligomannate is not marketed outside of China, but a similar phase 3 clinical trial is underway in North America with trial completion expected in 2026. A safety analysis found that the overall incidence of adverse reactions did not differ significantly between those getting the active and placebo groups. Tempering enthusiasm is the shady history of Shanghai Green Valley Pharmaceutical Company, accused of a “whirlpool of … bribery and fraud” for illegally marketing supposed anti-cancer miracle drugs. A leading Chinese academic suggested oligomannate could “become the largest fraud case in China in the 21st century.” The lead developer of oligomannate joined hundreds of other Chinese researchers who have been accused of data falsification, though a Chinese Ministry of Science and Technology investigation concluded that only a “small amount of misused pictures were found.”