The New and the Old in Alzheimer’s Treatment
Carina Peritore

The New and the Old in Alzheimer’s Treatment

Renewed interest in a “failed” drug and a rookie treatment debuts in China

Following a string of disappointing clinical results, a new compound called oligomannate has come to the forefront of Alzheimer’s news. Could this be getting our attention because of the recent failures in Alzheimer’s research, or are we hopeful this alternate therapy may be the answer to our quest for a cure? Perhaps it is a combination of both, but recent events have left Alzheimer’s researchers reeling.

Last year Biogen and Eisai ended late-stage trials of the experimental Alzheimer’s drug aducanumab. According to a review article in Nature Neurology, the failure of aducanumab forces us to confront hard questions: 1) We must reconsider the hypothesis that decades long build-up of amyloid beta plaques helps initiate the cognitive symptoms of the disease, 2) Most of the patients included in the aducanumab trial may have been too symptomatic and too far along in the disease progression to have benefitted from the treatment, 3) Aducanumab does not sufficiently clear soluble amyloid beta-oligomers which many studies have concluded may be synaptotoxic and microglia-stimulating, and 4) Disease modifications for AD may only be achieved through combination therapy.

Biogen has since announced that they plan to restart research on aducanumab. Why the reversal? The resurgence of interest is due to new analyses factoring in the dosage needed to cross the blood-brain-barrier and the duration of treatment, as well as including all trial participants and expanding its data set.

New pathways in AD research

Meanwhile the quiet workings of independent labs all over the world are advocating other targets of interest and alternate routes of treatment. Investigators are looking at clearance of tau using antibodies, vaccines, anti-sense oligonucleotides, or gene editing. Others are trying to understand the role of microglia and astrocytes and how these cells can change pre-symptomatic AD. These alternate avenues offer potential for developing chronic anti-inflammatory therapies such as the oligomannate muse.

It has been well-known that inflammation was a key driver of AD, for decades. In fact, when I interviewed for a scientist position at Roche Pharmaceuticals in 2000, the head of the PK/PD group told me about his grandmother who was suffering from dementia because of AD and proposed that AD was a disease of inflammation.

It wasn’t until recently that I’ve heard this hypothesis gain traction. In fact, there is a history of microbial links to AD, whether it be bacterial or common viral infections such as Herpes Simplex Virus Type 1 (HSV1). Hypotheses about AD may not only include amyloid plaques, tau tangles, and inflammation but also infection. As early as the 1990’s three laboratories in three different countries, each studying different organisms, had implicated human pathogens in the etiology of AD. This was outside the theoretical mainstream at the time: the concept that viruses or microbials have a direct effect on the downstream events leading to amyloid or tau build-up.

A seaweed-derived compound

Oligomannate provides a reprieve from the traditional focus while paying attention to one particular aspect of the disease that has been neglected, namely the microbiome. Oligomannate is a mixture of oligosaccharides derived from seaweed which has been shown to adjust the microbiome in mice. This compound was invented by Geng Meiyu’s team at the Shanghai Institute of Materia Medica at the Chinese Academy of Sciences.

Preclinical studies show that oligomannate reconditions dysbiosis of gut microbiota, inhibits the abnormal increase of intestinal flora metabolite, modulates peripheral and central inflammation, reduces amyloid protein deposition and tau hyperphosphorylation and improves cognitive function. Although all of this recently accumulated data suggest that the gut microbiota associates with AD pathogenesis, it is not yet clear how alterations in the gut microbiota mechanistically contribute to different aspects of AD pathology.

These published findings from China support the idea that modulation of the gut microbiota may provide hope and support for research in that direction. While promising, we are still waiting to hear of the results from a second phase 3 trial to investigate its clinical effects in larger and more diverse populations.

Furthermore, the field’s response has been met with skepticism. Some researchers say that the same gut bacteria that produce pro-inflammatory responses were more abundant with treatment of oligomannate. Others postulate that the mere definition of inflammation has its own controversy because pro-inflammatory cytokines are produced during inflammation, but then anti-inflammatory cytokines are also produced to clean up or resolve that inflammation.

It is clear we need a better understanding of Alzheimer’s mechanism of action. We don’t want to run into the same problem as we did for aducanumab, where it turns out only treats favorably those in the early stages of the disease. Will oligomannate successfully adjust the microbiome to a less inflammatory state only to leave prior damage to the brain irreversible? Time will tell.