The Fatty Enigma: Investigating a New Culprit in Alzheimer's Disease

Wednesday - March 20 2024, 08:49 UTC - 8 months ago

A recent study has uncovered a potential new culprit in Alzheimer's disease: fatty bubbles inside immune cells in the brain. These bubbles, which accumulate in those with a specific gene variant, may be linked to the development of the disease. This could open up new avenues for therapeutic development in the fight against Alzheimer's.

At the turn of the 20th century, Dr. Alois Alzheimer noticed peculiar changes in a freshly removed brain. The brain had belonged to a 50-year-old woman who gradually lost her memory and struggled with sleep, increased aggression, and eventually paranoia.

Under the microscope, her brain was littered with tangles of protein clumps. Curiously, shiny bubbles of fat had also accumulated inside brain cells, but they weren’t neurons—the brain cells that spark with electricity and underlie our thoughts and memories. Instead, the fatty pouches built up in supporting brain cells called glia.

Scientists have long thought toxic protein clusters lead to or exacerbate Alzheimer’s disease. Decades of work aimed at breaking down these clumps has mostly failed—earning the endeavor the nickname "graveyard of dreams." There has been a recent win. In early 2023, the US Food and Drug Administration approved an Alzheimer’s drug that slightly slowed cognitive decline by inhibiting protein clumps, although amid much controversy over its safety.

A growing number of experts are exploring other ways to battle the mind-eating disorder. Stanford’s Dr. Tony Wyss-Coray thinks an answer may come from the original source; Alois Alzheimer’s first descriptions of fatty bubbles inside glia cells—but with a modern genetic twist.

In a new study, the team targeted fatty bubbles as a potential driver of Alzheimer’s disease. Using donated brain tissue from people with the disorder, they pinpointed one cell type that’s especially vulnerable to the fatty deposits—microglia, the brain’s main immune cells.

Not all people with Alzheimer’s had overly fatty microglia. Those who did harbored a specific variant of a gene, called APOE4. Scientists have long known that APOE4 increases the risk of Alzheimer’s, but the reason why has remained a mystery.

The fatty bubbles may be the answer. Lab-made microglia cells from people with APOE4 rapidly accumulated bubbles and spewed them onto neighboring cells. When treated with liquids containing the bubbles, healthy neurons developed classical signs of Alzheimer’s disease.

The results uncover a new link between genetic risk factors for Alzheimer’s and fatty bubbles in the brain’s immune cells, the team wrote in their paper.

"This opens up a new avenue for therapeutic development," the University of Pennsylvania’s Dr. Michal Haney, who was not involved in the study, told New Scientist.

The Forgetting Gene .

Two types of proteins have been at the heart of Alzheimer’s research.

One is beta-amyloid. These proteins start as wispy strands, but gradually they grasp each other and form large clumps that gunk up the outside of neurons. Another culprit is tau. Normally innocuous, tau eventually forms tangles inside neurons that can’t be easily broken down.

Together, the proteins inhibit normal neuron functions. Dissolving or blocking these clumps should, in theory, restore neuronal health, but most treatments have shown minimal or no improvement to memory or cognition in clinical trials.

Meanwhile, genome-wide studies have found a gene called APOE is a genetic regulator of the disease. It comes in multiple variants: APOE2, APOE3, and APOE4. The former two are considered the "good" variants and seem to protect against Alzheimer’s. The APOE4 variant is the "bad" one, significantly increasing the risk of developing the disease.