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Alzheimer’s Disease: It’s Not All in Your Head

Recent studies have linked Alzheimer’s to the gut microbiome.

By Jeeya Sharma

Whistles of pressurized steam hammer against a metal shield. An autoclave oven operates at 250 degrees Fahrenheit for three hours, exterminating any living thing inside. It is being used to purify a life-sustaining item: water. A masked carrier, enveloped in a disinfected hazmat suit, must pass through multiple sanitation stations to deliver this package to another room. A lingering scent of bleach engulfs the atmosphere. This room is quiet. A soft, rhythmic patter of small paws and intermittent, high-pitched squeaks produce a distant hum. The mice, small, black bodies speckled across an aseptic, white backdrop, scurry across their cages. 

These germ-free mice reside in hermetically sealed enclosures, airtight containers that isolate them from the rest of the world. There, they breathe sterile air. When their decontaminated food and water are delivered to them, the mice can rest assured that they have what they need to survive. However, these mice may never realize that they are crucial to bettering the understanding of a devastating neurodegenerative disease. 

Untangling the causes of Alzheimer’s

Alzheimer’s disease, an age-associated brain disorder that affects 6 million Americans, is caused by a buildup of misshapen proteins in the brain. These plaques, called amyloid-beta and tau, entangle themselves with the brain’s neurons, causing the neurons to malfunction and die. An affected individual is left with lost memories and in a state of constant confusion.

The cause of this neurodegeneration puzzles scientists as they search the brain for answers. Now, researchers have found that the cause of Alzheimer’s may not be all in your head. Instead, it may begin with your gut. 

A study published in Gut in January 2022 by a team of Emory University researchers establishes a causal link between gut microbiome composition and neuroinflammation that may lead to Alzheimer’s. The gut microbiome is a collection of trillions of bacterial, fungal, and viral microorganisms that inhabit the digestive tract and collaborate to help digest food and protect its environment from pathogens. These microbiota are a core component of the gut-brain axis, the communication network between the gut and the brain. Thus, they have a major effect on the health of an individual, including their propensity to develop Alzheimer’s disease. By inoculating germ-free mice with microbiota from diseased patients, researchers were able to demonstrate a tie between the gut microbiome and the onset of Alzheimer’s disease. 

Photo by Silje Roseneng on Unsplash

Understanding the human-microbe relationship

“We, as humans, live in intimate contact with bacteria, on every exposed surface of our bodies, and… we form a superorganism. We live as two peaceable kingdoms together: the human and the microbes,” says Rheinallt Jones, an associate professor in the department of pediatrics at Emory University and Director of the Emory Gnotobiotic Animal Core, “But, if the microbe population would change—if there’s disquiet between the two kingdoms—then, that could predispose or that could lead to adverse physiological events.”  

The mice began to present signs of Alzheimer’s pathology after fecal microbiome transplants from Alzheimer’s patients. The microbiome-colonized mice exhibited increased amyloid-beta, tau, and neurofibrillary tangle build-up. They also experienced increased activation of microglia, or neuronal defenders of the brain, and spatial memory defects. As such, the researchers found that the gut microbiota was sufficient to reproduce the Alzheimer’s phenotype. Furthermore, the scientists were able to elucidate some of the mechanisms through which this process happens. 

“They show that these polyunsaturated fatty acids are sufficient to drive these pathologies,” says Timothy Sampson, an Assistant Professor in the Emory School of Medicine and expert in neurodegenerative diseases.

Gut dysbiosis in genetically susceptible organisms can initiate an inflammatory cascade through polyunsaturated acid metabolites, or fats like Omega-6 and Omega-3. These metabolites can travel to and infiltrate the brain. Concomitant neuroinflammation triggers additional inflammation that promotes the development of Alzheimer’s disease. The study finds that short-chain fatty acids, another microbiota-associated metabolite, also drive neuroinflammation; however, they may not exhibit the same phenotype in humans or mice with more developed immune systems. Sampson says, “Short-chain fatty acids are detrimental in germ-free mice because their immune systems are underdeveloped.” 

Illuminating new pathways for drug development

Regardless, the study shows that the microbiome plays a part in Alzheimer’s pathology. These results could inspire drug development to manage neurodegenerative disease through bacteria-targeting treatments. However, there are hurdles to these approaches. For example, antibiotics eliminate the entire gut microbiome, so their use would also deplete commensal microbes and their benefits. Probiotics would not eliminate pathogenic bacteria, but instead, they would add more beneficial microbes that may help combat the negative effects of other microbes. Fecal microbiome transplants, on the other hand, would replace one’s microbiome with an entirely new—and hopefully better—one. Therefore, a multi-pronged approach may be required to treat Alzheimer’s, but gut bacteria-specific therapies still exhibit promise in promoting healthy aging. 

This study opens a new avenue of explanation for the development and potential treatment of Alzheimer’s. But to continue, scientists must first identify what microbiota are commensal and which ones are pathogenic. Many steps remain until these findings can be taken from the mouse house to the clinic. The question of what exact microbe or set of microbes causes this pathogenic pathway is the next challenge in the field. “Poetically, you would think about how you separate the dancer from the dance. They’re entangled,” says Jones.