Researchers at the University of Florida found that glucosamine use was associated with a greater likelihood that mild cognitive impairment would progress to dementia. Mild cognitive impairment, often shortened to MCI, describes measurable problems with memory or thinking that are greater than expected with normal aging but do not necessarily interfere substantially with everyday life.

The findings come from a large retrospective analysis of patient health records, supported by experiments involving human brain tissue and mouse models of Alzheimer’s disease. The results remain preliminary and will need to be tested in a human clinical trial, but the researchers say they add to growing evidence that disrupted metabolism may play an important role in neurodegeneration.

The study was published in Nature Metabolism.

A Popular Supplement Comes Under Scrutiny

“In the United States, there are about 7 million people living with Alzheimer’s and millions more with related dementias such as Lewy body or frontotemporal dementia,” said senior author Ramon Sun, Ph.D., director of the Center for Advanced Spatial Biomolecule Research and associate director for innovation of UF’s McKnight Brain Institute. “A lot of these people actively take an over-the-counter supplement that could be making their disease progression worse.”

Glucosamine is widely sold without a prescription and is especially popular among older adults who take it for joint discomfort and joint health. Because of how commonly it is used, the researchers wanted to know whether it might influence Alzheimer’s disease and related dementias, known as ADRD.

Working with Yi Guo, Ph.D., and Jiang Bian, Ph.D., the team used artificial intelligence to analyze deidentified UF Health records collected from 2012 to 2024.

The researchers focused on patients diagnosed with either ADRD or mild cognitive impairment, or MCI. In both groups, 8% of patients reported using glucosamine. That included 1,896 people with ADRD and 2,750 people with MCI.

Glucosamine Linked to Dementia Progression

After accounting for age, sex and demographics, the researchers found that glucosamine use was associated with a 25% higher likelihood that mild cognitive impairment would progress to dementia.

Among people who already had ADRD, glucosamine use was also associated with a 25% higher mortality risk, meaning a greater likelihood of death during a defined period of time.

The researchers did not observe that mortality association in the MCI group. That difference suggests glucosamine may have a stronger effect once dementia is already established.

Importantly, the health record findings do not show that glucosamine itself causes dementia to progress. Observational studies can reveal associations, but other differences between people who take a supplement and those who do not may contribute to the results.

“The electronic health record data are very provocative,” said Matt Gentry, Ph.D., chair of UF’s Department of Biochemistry and Molecular Biology and a study co-author. “While it’s an association and not proof of causality, it does raise an important clinical question that now deserves much more attention.”

A Metabolic Pathway May Help Explain the Link

The researchers also uncovered evidence of a biological mechanism that could help explain the association.

Their work points to a metabolic pathway involving the attachment of sugar structures to proteins. This process is a normal and important part of cell biology, but the researchers found signs that it becomes excessively active in Alzheimer’s disease.

Sun said that abnormal activity in this pathway could eventually become a target for new treatments.

“Our results suggest that altered metabolism is a significant contributor to Alzheimer’s progression and, in addition, addressing the metabolic defect could be an important complement to approaches focused on Alzheimer’s plaques and tangles,” Sun said.

Plaques and tangles are two of the best known features of Alzheimer’s disease. Plaques are abnormal deposits of a protein called amyloid beta that accumulate between brain cells, while tangles are twisted forms of the tau protein that develop inside neurons. Much Alzheimer’s research has traditionally focused on these abnormalities, but scientists are increasingly studying additional processes that may contribute to the disease.

Mapping Thousands of Molecules in the Brain

A spatial technology developed in Sun’s laboratory helped researchers examine the metabolic changes in much greater detail.

“This technology allows us to examine thousands and thousands of molecules created when the body breaks down food or drugs and to uncover intricate pathways that otherwise would stay hidden,” Sun said.

The team then focused specifically on glucosamine. Glucosamine is a naturally occurring, sugar-related molecule that can cross the blood-brain barrier, the protective boundary that tightly controls which substances can move from the bloodstream into brain tissue.

Once inside the brain, glucosamine can enter biochemical pathways that construct complex sugar structures and attach them to proteins. Commercial glucosamine supplements can be produced from materials including shellfish shells or corn.

According to the researchers, the effects of glucosamine may depend heavily on the biological environment in which it is acting. A healthy brain and a brain affected by Alzheimer’s may therefore respond differently to the same molecule.

The Alzheimer’s brain appeared to be particularly vulnerable to this metabolic pathway.

Mouse Experiments Point to a Possible Mechanism

To explore the mechanism more closely, the scientists studied genetically modified mice.

Glucosamine significantly increased the attachment of sugar residues to proteins inside cells. At the same time, glucosamine-treated mice developed worse deficits in “social memory” — or memory of recognition — compared with the other animals.

When the researchers used a chemical treatment to suppress the sugar attachment process, memory performance improved.

That experiment suggested that excessive sugar tagging could play a direct role in the memory problems seen in the animals rather than simply occurring alongside them.

Human Alzheimer’s Brain Tissue Shows the Same Pattern

The researchers next examined human brain tissue with Stefan Prokop, M.D.

Brain specimens from people with Alzheimer’s disease, provided by the UF Neuromedicine Brain and Tissue Bank, showed significantly more sugar attachment than tissue from normal controls.

Combined with the mouse experiments and health record analysis, the findings suggest that abnormal metabolism may be more than a secondary consequence of Alzheimer’s disease. The researchers reported that it could instead contribute to the disease process itself.

“Proteins are the cell’s molecular machines, and many of them need sugar tags added in just the right way to fold correctly, travel to the right place and do their jobs,” Gentry said. “What we found in Alzheimer’s is that this sugar-tagging system appears to be overactive. The Alzheimer’s brain is adding too many of these sugar structures, and this seems to contribute to the disease rather than protect against it.”

The results raise a potentially important question about glucosamine use among people with cognitive impairment or dementia, but they do not yet establish that people should stop taking the supplement. A controlled human clinical trial will be needed to determine whether glucosamine directly accelerates Alzheimer’s progression and, if so, which patients may be most vulnerable.

The researchers examined how depression, smoking, obesity, sleep problems, and other health conditions are connected with difficult-to-treat rheumatoid arthritis.

Rheumatoid arthritis is a chronic autoimmune disease in which the immune system mistakenly attacks the joints, leading to pain, swelling, and stiffness. In Hungary alone, it affects tens of thousands of people. Most patients respond well to treatment, but 6-28 percent fall into the so-called “difficult-to-treat” group because they do not achieve lasting remission despite therapy.

According to the studies in Nature Reviews Rheumatology and The Lancet Rheumatology, these additional health problems may do more than simply occur alongside rheumatoid arthritis. They may also contribute to keeping symptoms active.

A Vicious Cycle of Pain, Mood, and Sleep

Pain and depression, for example, can reduce physical activity, contribute to weight gain, and worsen both sleep and mood. Those changes can then intensify pain and make daily activities more difficult, creating a difficult-to-break “vicious cycle.”

The researchers also developed a new model that could improve care for patients whose rheumatoid arthritis remains difficult to manage. Under the widely used “treat-to-target” approach, doctors regularly track measurable indicators of disease activity. If inflammation is not reduced enough, treatment is adjusted, such as by increasing the medication dose or switching to another drug.

The team argues that this same approach can also serve as a kind of “early warning system.” If measurable signs of inflammation improve but symptoms remain, that may indicate the pain or fatigue is not being caused solely, or perhaps at all, by ongoing inflammation.

Looking Beyond Inflammation

“When target values improve but the patient still suffers from pain and fatigue, it is worth taking a step back. In such cases, instead of automatically prescribing more medication, doctors should look for what is maintaining the symptoms – whether it is chronic pain syndrome, depression, sleep disorders, or obesity,” said Dr. György Nagy, head of the Department of Rheumatology and Immunology at Semmelweis University.

The researchers say they have seen this approach improve outcomes in difficult-to-treat patients. In many cases, it may also strengthen the doctor-patient relationship by focusing treatment more closely on what is actually driving the patient’s symptoms.

A Model With Growing International Influence

The team’s model has gained substantial international attention. Publications that introduced the concept of “difficult-to-treat” disease and the related treatment strategy have already been cited more than a thousand times by other researchers.

The definition is now used worldwide not only for rheumatoid arthritis, but also in discussions of other diseases.

AI Could Help Personalize Treatment

The researchers are now looking toward the next stage of the work. Alongside their own studies, they plan to participate in projects that use artificial intelligence to develop more effective treatments for people with rheumatoid arthritis.

“With AI-based pattern recognition, we could identify subgroups among patients, and with the help of these data we could create more effective, almost personalized treatment strategies for them,” explained Dr. Lilla Gunkl-Tóth, PhD student at Semmelweis University and first author of the publications.

Research led by Brandon Boor at Purdue University found that fragrance compounds released by both conventional cleaners and botanical essential oil-based products can rapidly react indoors and generate nanoparticles. If inhaled, some of these extremely small particles can penetrate deep into the lungs.

The researchers say exposure can be reduced by choosing unscented products, improving ventilation with exhaust fans or open windows, and avoiding devices that generate ozone while scented cleaning products are being used.

The researchers presented their results at the fall meeting of the American Chemical Society (ACS) during the “Healthy Indoor Spaces: Bridging the Microbiome and Chemistry” symposium in McCormick Place.

“Importantly, cleaning removes viruses and bacteria from surfaces, but it can also generate invisible air pollution. There’s no visible dust or smoke in the air, but these particles are forming.” — Brandon Boor

Cleaning Can Create Invisible Nanoparticles

“We showed that indoor ozone reactions with fragrances from cleaning produce nanoparticles that carry a respiratory dose comparable to, or greater than, what you would experience from standing outside along a busy road,” says Boor, an Assistant Professor of Civil and Construction Engineering at Purdue University who studies indoor air quality. “The particles are different in terms of their composition, but the total dose can be higher. You’re not seeing smoke, dust, or haze in the air. Instead, you think the air smells great so it must be clean.”

Boor began investigating how cleaning agents and chemical disinfectants affect indoor environments during the COVID-19 pandemic with his colleague Nusrat Jung, a Purdue Assistant Professor of Civil and Construction Engineering. One feature quickly stood out: many of the products people use to clean and disinfect indoor spaces contain strong fragrances.

“That’s often to create a pleasant smellscape in the indoor space,” says Boor. “But clean air should not smell like highly concentrated citrus fruit. It should not really smell of anything.”

Scientists who study the atmosphere have long known that compounds released by plants can react with ozone. Terpenes such as pinene from pine trees, for example, can participate in reactions that generate tiny airborne particles. Over time, those particles can combine and grow until they become large enough to help seed clouds.

That chemistry proceeds relatively slowly in forests because the amount of terpenes in outdoor air is generally low.

Cleaning Products Release High Levels of Terpenes

Indoors, the situation can be very different. Scented cleaners release terpenes when fragrance compounds evaporate from sprayed droplets or cleaned surfaces.

Cleaning liquids commonly contain compounds including pinene, limonene (lemon), thymol (thyme), and linalool (lavender). Their concentrations during cleaning can be far higher than levels typically measured outdoors. Boor says airborne terpene concentrations inside a room during cleaning can rise to tens or even hundreds of times those found in a forest.

To examine what happens under realistic conditions, the researchers tested scented conventional liquid products as well as botanical-containing disinfectant sprays and wipes inside a model home on Purdue’s campus.

The small house includes a functional kitchen, wood flooring, and a bathroom, allowing the researchers to recreate ordinary household cleaning activities. Their experiments showed that the same basic chemistry responsible for nanoparticle formation outdoors can occur indoors much more rapidly and at much higher concentrations, with potentially important consequences for human exposure.

Billions or Trillions of Particles Can Form

Routine tasks such as mopping floors, spraying countertops, and wiping surfaces with scented products generate billions or trillions of particles, with the total depending on the product.

Most were nanoparticles or ultrafine particles measuring only 1-30 nanometers across. Because particles this small often fall outside the detection range of at-home air quality monitors, people may have no indication that particle concentrations have risen.

The researchers found that ordinary cleaning can temporarily push ultrafine particle levels above those measured outdoors.

Their tiny size is important from a health perspective. Ultrafine particles can settle throughout the respiratory tract and reach deep regions of the lungs. Once there, they can contribute to irritation and inflammation in the respiratory system. Some may also have the potential to enter the bloodstream.

One of the biggest surprises was the speed of the process. Particle formation and growth occurred within just minutes.

“By the time you finish cleaning up an indoor space, you’ve already formed a lot of nanoparticles and inhaled them,” says Boor.

Ozone Can Intensify Indoor Particle Formation

More recently, Boor and Ernest Blatchley, a Professor at Purdue, studied what happens when scented surface cleaners are used at the same time as germicidal far-UV (UV-C) lamps designed to disinfect indoor air.

The combination created particularly favorable conditions for nanoparticle formation.

The lamps interact with oxygen in the air and produce ozone. During experiments in the tiny home, ozone concentrations increased to roughly 20 to 40 parts per billion. Those levels were comparable to, although somewhat below, the outdoor ozone concentrations measured when the experiments were performed.

With both elevated ozone and high concentrations of terpenes present, nanoparticle production became even more intense. That combination raised additional concerns about the amount of particulate matter occupants could inhale.

How to Reduce Exposure While Cleaning

Boor emphasizes that the goal is to help consumers make informed choices rather than discourage cleaning. Cleaning remains important for removing viruses and bacteria from surfaces, but several simple measures may reduce exposure to the secondary pollution produced during the process.

The researchers recommend:

• Choose low-fragrance or fragrance-free products.
• Avoid applying several scented products in the same cleaning session.
• Run exhaust fans or open windows to ventilate the space.
• Do not simultaneously clean surfaces with scented products while using ozone-generating devices, such as far UV-C lamps.

“Importantly, cleaning removes viruses and bacteria from surfaces, but it can also generate invisible air pollution,” says Boor. “There’s no visible dust or smoke in the air, but these particles are forming.”

Boor thanks all the graduate students who have worked with him in the tiny house experiments along with the support of undergraduate students.

The research was funded by a National Science Foundation Faculty Early Career Development Program (CAREER) grant and the Alfred P. Sloan Foundation.

Title Indoor atmospheric nanoparticle formation from scented cleaning products

Abstract Scented volatile chemical products, including surface cleaning agents and botanical disinfectants, are widely used indoors and represent a major source of reactive organic emissions. These products are routinely applied in homes and workplaces for surface cleaning and disinfection to reduce the presence of viruses and bacteria. However, their role in driving indoor atmospheric chemistry and nanoparticle formation remains poorly constrained. This presentation investigates the impact of scented cleaning product use on airborne nanoparticle nucleation, growth, and human exposure to secondary pollutants in indoor environments. Field and laboratory experiments were conducted in controlled residential and office settings using real-time, high-resolution measurements of volatile organic compounds and nanoparticle size distributions extending to the nanocluster aerosol (1-3 nm) regime. Surface cleaning and disinfection activities produced rapid increases in terpene and terpenoid mixing ratios (10-1,000 ppb), often exceeding levels observed in outdoor forested environments. These compounds reacted with indoor oxidants, particularly ozone, to initiate intense nanoparticle nucleation and growth events. Observed nucleation rates (~105 cm^-3 s^-1) and condensational growth rates (up to 300 nm h^-1) exceeded typical outdoor values by orders of magnitude, resulting in transient indoor nanoparticle number concentrations of 10⁵-10⁸ cm^-3. Rapid nanoparticle growth enabled survival to sizes that efficiently deposit throughout the human respiratory system, yielding inhalation dose rates comparable to or exceeding those from primary combustion sources such as traffic emissions. Both conventional and botanical cleaning products generated complex multiphase exposure scenarios involving reactive gases and secondary organic aerosol. These findings identify indoor surface cleaning and disinfection as key drivers of indoor atmospheric nanoparticle formation and highlight the need for improved building ventilation, air cleaning, and product formulation to mitigate exposure to secondary pollutants.