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Microbiome studies explore why more women develop Alzheimer’s disease

Two new studies from the University of Chicago investigate the roles of the gut microbiome and estrogen in the differing rates of Alzheimer’s disease among women and men.

By Matt Wood (Assistant Director of Communications, Biological Sciences Division)

According to the Alzheimer’s Association, almost two-thirds of Americans with Alzheimer’s dementia are women. While some of this discrepancy can be attributed to women living longer than men on average, researchers believe biological factors play a role as well.

A pair of new studies from the University of Chicago explore sex-specific differences in the development of Alzheimer’s-like symptoms in mice, including the impact of estrogen, the primary female reproductive hormone, on the formation of amyloid plaques and inflammation in the brain — two hallmark symptoms of the disease. The research also strengthens evidence of the gut microbiome’s role in mediating these symptoms, providing clues that could someday help develop treatments.

Clues pointing to the microbiome

Alzheimer’s disease is characterized by the formation of amyloid plaques, or clumps of the protein amyloid beta (Aβ) that accumulate in the brain. The disease also activates immune cells present in the brain known as microglia, which can help remove amyloid plaques but may also exacerbate the disease by causing inflammation.

In 2019, a research team led by Sangram Sisodia, PhD, the Thomas A. Reynolds Sr. Family Professor of Neurobiology at UChicago, treated mouse models of Alzheimer’s disease with a cocktail of antibiotics during the second week of life. The antibiotics lessened the formation of amyloid plaques and microglia activation in males — but surprisingly, not female mice — by 3 months of age. Although this antibiotic regimen initially wipes out all gut bacteria, the gut becomes repopulated with numerous additional bacterial species over the next three months.

Sisodia reasoned that the microbiome must play a major role in these changes in amyloid deposition and neuroinflammation. To prove that the improvements in Alzheimer’s symptoms were caused by alterations in the gut microbiome, they also transplanted fecal matter from untreated mice into antibiotic-treated animals. This procedure restored the gut microbiome and caused an increase in amyloid plaque formation and microglial activation. These findings have since been confirmed and reported in several labs around the country.

Sex-specific microbiome changes

In the first of new papers, published February 17, 2024, in Molecular Neurodegeneration, Sisodia and his colleagues tested the effects of a new drug compound called sodium oligomannate, or GV-971, on the formation of amyloid deposits and neuroinflammation. The compound was originally derived from brown seaweed by the Chinese pharmaceutical company Shanghai Green Valley Pharmaceuticals. In the company’s testing, GV-971 reduced amyloid deposits and neuroinflammation in Alzheimer’s mouse models. The compound has also undergone Phase III clinical trial testing in China and is now clinically approved for patients with Alzheimer’s.

When Sisodia and his team tested GV-971 on a mouse model of Alzheimer’s, they saw a significant drop in amyloid deposits, even at the lowest doses, and a reduction in inflammatory markers in the microglia—but again, these changes were only observed in male animals. They also noted significant changes in the composition and abundance of several types of gut bacteria in male mice, but fewer changes in the microbiome of females.

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