Alzheimer’s disease is widely believed to be caused by accumulating amyloid plaques in the brain, which trigger cascading effects that cause damage. But efforts to reduce amyloid plaques haven’t reversed cognitive decline, causing some to wonder whether something else is going on.

Leyla Akay, director of biology at the Boston area startup TAC Therapeutics, is among them — and thinks that “something else” might be fat metabolism, or, more precisely, disruptions to normal fat metabolism in the brain.

Akay, who spoke at the Radcliffe Institute for Advanced Study on Thursday, pointed out that the recently approved Alzheimer’s drug donanemab reduces amyloid beta plaques in the brain, but that it only slows cognitive decline and doesn’t reverse it.

“Ultimately, these patients are declining,” said Akay. “It’s fair to ask if we can do better and ask, ‘Are there other potential causes of biological mechanisms contributing to Alzheimer’s disease?’”

During Akay’s doctoral work at MIT, she zeroed in on the APOE4 gene, a mutation of APOE3 and major risk factor for developing Alzheimer’s disease. APOE4 plays a role in lipid transport in the brain but is worse at the task than APOE3. The result is lipids accumulating inside of brain cells and disruption of nerve cells’ fatty myelin coating, which could affect how nerve signals move through the brain.

When Akay’s lab discovered that inhibiting a molecule called GSK3 beta reduced lipid accumulation inside of brain cells and improved myelination, they started TAC Therapeutics to develop the idea further.

Akay told the audience for the panel, which was part of Radcliffe’s Next in Science series, that early results are promising but there’s a lot of work still to be done.

“A lot of work ahead” was also a theme for other speakers at the event, who spoke about modifiable risk factors for Alzheimer’s, the possibility of social drivers influencing the condition, and how work continuing on the amyloid beta front includes a focus on the second step in the destructive cascade: the development of tangles of a protein called tau in the brain.

The event was moderated by Immaculata De Vivo, professor of medicine at Harvard Medical School, professor of epidemiology at the T.H. Chan School of Public Health, and Radcliffe’s faculty co-director of the sciences. De Vivo said dementia — with Alzheimer’s as the leading cause — already affects 55 million people in the world, and that number is set to almost triple by 2050. Despite that gloomy forecast, De Vivo hailed the research moving ahead on several fronts that continues to push the frontiers of knowledge about the feared condition.

She hailed advances in molecular and cellular neuroscience, genetics, and genomics, in our understanding of how environmental conditions increase risk, and how clinical trials and advances in prevention are working to delay onset and slow progression.

“This is a moment of real possibility,” De Vivo said. “Our speakers today are advancing our understanding of dementia from very different vantage points: epidemiology and social drivers of health, clinical research and prevention, neurobiology and model systems, and the role of lipids — fats — and genetics in neurodegeneration.”

Cara Croft, senior lecturer in neuroscience at Queen Mary University of London described work in her lab using mice and naked mole-rats to explore the role of the protein tau in Alzheimer’s disease. Tau accumulates in fibrous tangles in the brain and is believed to be triggered by the initial accumulation of amyloid beta plaques. A key part of her work is examining how neurons can sometimes unravel tau tangles, allowing them to be cleared rather than accumulate.

“We know that proteins can unravel and unclump and that’s something that we want to boost,” Croft said. “Some neurons already have this fast tau unraveling and we want to normalize them all to have this really fast tau unraveling with the idea that this could be a future treatment for Alzheimer’s disease or dementia.”

Reducing risk of developing Alzheimer’s in the first place is possible and may depend in part on our legs and our appetites. Jennifer Gatchel, assistant professor of psychiatry at HMS and Massachusetts General Hospital, said recent work has shown that there is such a thing as a brain-healthy diet. The Mediterranean diet with legumes, fish, and olive oil; the DASH diet focused on lowering blood pressure; and the MIND diet, which combines elements of the two, have all shown benefits in lowering Alzheimer’s risk. Gatchel also pointed to recent work out of MGH that found that physical activity can affect risk. Those who walked more had reduced risk of the condition. And, though walking more was associated with even lower risk, even the lowest level, 3,000 steps per day, brought positive benefits.

“Even small incremental changes can actually have biological effects on our brain, so it doesn’t have to be all or nothing,” Gatchel said. “That was a very, very exciting finding.”

Our position in society may also play a role in our Alzheimer’s risk, according to Ganga Bey, assistant professor at the University of North Carolina Chapel Hill. Bey’s research focuses on how the stressors that come with social hierarchy, made up of socioeconomic factors such as race, gender, and ethnicity, can increase Alzheimer’s risk through stress, diet, blood pressure, and other physiological factors. The result, Bey said, is that Black Americans have twice the risk of Alzheimer’s, and Hispanics 1.5 times the risk, as non-Hispanic white Americans.

“Alzheimer’s disease and related dementias are patterned along clear racial, ethnic, and socioeconomic lines. Some sex or gender disparities exist as well but they are less consistently observed,” Bey said. “What in the environment that is doing all these things and causing so much disease, but is so poorly understood? What is it exactly that we’re referring to and how does it influence the behavior of our genes?”