Scientists from Columbia University, the Columbia Mailman School of Public Health and New York University led the analysis, which addresses a widespread health concern. Naturally occurring arsenic in groundwater remains a significant challenge across the world. In the United States, more than 100 million people depend on groundwater that can contain arsenic, particularly those using private wells. Arsenic continues to be one of the most common chemical contaminants in drinking water.

“We show what happens when people who are chronically exposed to arsenic are no longer exposed,” said co-lead author Lex van Geen of the Lamont-Doherty Earth Observatory, part of the Columbia Climate School. “You’re not just preventing deaths from future exposure, but also from past exposure.”

Two Decades of Data Strengthen the Evidence

Co-lead author Fen Wu of NYU Grossman School of Medicine said the findings offer the clearest proof yet of the connection between lowering arsenic exposure and reduced mortality risk. Over the course of two decades, the researchers closely tracked participants’ health and repeatedly measured arsenic through urine samples, which strengthened the precision of their analysis.

“Seeing that our work helped sharply reduce deaths from cancer and heart disease, I realized the impact reaches far beyond our study to millions in Bangladesh and beyond now drinking water low in arsenic,” said Joseph Graziano, Professor Emeritus at Columbia Mailman School of Public Health and principal investigator of the NIH-funded program. “A 1998 New York Times story first brought us to Bangladesh. More than two decades later, this finding is deeply rewarding. Public health is often the ultimate delayed gratification.”

Clear Drop in Risk When Arsenic Exposure Falls

People whose urinary arsenic levels fell from high to low had mortality rates that matched those who had consistently low exposure for the entire study. The size of the drop in arsenic was closely tied to how much mortality risk declined. Those who continued drinking high-arsenic water did not show any reduction in chronic disease deaths.

Arsenic naturally accumulates in groundwater and has no taste or smell, meaning people can drink contaminated water for years without knowing it. In Bangladesh, an estimated 50 million people have consumed water exceeding the World Health Organization’s guideline of 10 micrograms per liter. The WHO has described this as the largest mass poisoning in history.

From 2000 to 2022, the Health Effects of Arsenic Longitudinal Study (HEALS) monitored thousands of adults in Araihazar, Bangladesh. The project tested more than 10,000 wells in a region where many families rely on shallow tube wells with arsenic levels ranging from extremely low to dangerously high.

Researchers periodically measured arsenic in participants’ urine, a direct marker of internal exposure, and recorded causes of death. These detailed data allowed the team to compare long-term health outcomes for people who reduced their exposure with those who remained highly exposed.

Community Efforts Created a Natural Comparison Group

Throughout the study period, national and local programs labeled wells as safe or unsafe based on arsenic levels. Many households switched to safer wells or installed new ones, while others continued using contaminated water. This created a natural contrast that helped researchers understand the effects of reducing exposure.

Arsenic exposure decreased substantially in Araihazar during the study. The concentration in commonly used wells fell by about 70 percent as many families sought cleaner water sources. Urine tests confirmed a corresponding decline in internal exposure, averaging a 50 percent reduction that persisted through 2022.

Reduced Exposure Brings Lasting Health Benefits

These trends held true even after researchers accounted for differences in age, smoking and socioeconomic factors. Participants who remained highly exposed, or whose exposure rose over time, continued to face significantly higher risks of death from chronic diseases.

The researchers compared the health benefits of lowering arsenic to quitting smoking. The risks do not disappear immediately but drop gradually as exposure decreases.

In Bangladesh, well testing, labeling unsafe sources, drilling private wells and installing deeper government wells have already improved water safety for many communities.

“Our findings can now help persuade policymakers in Bangladesh and other countries to take emergency action in arsenic ‘hot spots’,” said co-author Kazi Matin Ahmed of the University of Dhaka.

To reach more households, the research team is collaborating with the Bangladeshi government to make well data easier to access. They are piloting NOLKUP (“tubewell” in Bangla), a free mobile app created from more than six million well tests. Users can look up individual wells, review arsenic levels and depths, and locate nearby safer options. The tool also helps officials identify communities that need new or deeper wells.

Clean Water Investments Can Save Lives

The study shows that health risks can fall even for people who were exposed to arsenic for years. This highlights an important opportunity: investing in clean water solutions can save lives within a single generation.

“Sustainable funding to support the collection, storage and maintenance of precious samples and data over more than 20 years have made this critically important work possible,” said Ana Navas-Acien, MD, PhD, Professor and Chair of Environmental Health Sciences at Columbia Mailman School of Public Health. “Science is difficult and there were challenges and setbacks along the way, but we were able to maintain the integrity of the samples and the data even when funding was interrupted, which has allowed us to reveal that preventing arsenic exposure can prevent disease.”

The study team included researchers from Columbia University’s Mailman School of Public Health, the New York University Grossman School of Medicine, Lamont-Doherty Earth Observatory, Boston University School of Public Health, the Department of Geology at the University of Dhaka and the Institute for Population and Precision Health at the University of Chicago.

The HEALS project was launched by Columbia University through the National Institute of Environmental Health Sciences’ Superfund Research Program, with most U.S. collaborators based at Columbia when the study began.

Researchers at Arizona State University, working with partners at several institutions, now report that these effects may appear much earlier than expected. In young adults with obesity, the team identified biological markers linked to inflammation, liver strain and early injury to brain cells. These small but measurable shifts resemble patterns seen in older adults with cognitive impairment.

The study uncovered another important finding. Many of the young adults showed unusually low blood levels of choline, a nutrient essential for supporting liver health, regulating inflammation and protecting long-term brain function.

“This research adds to the growing evidence that choline is a valuable marker of metabolic and brain dysfunction — and reinforces the importance of sufficient daily intake, as it is essential for human health,” says Ramon Velazquez. “Several new reports published this month further link reduced blood choline levels to behavioral changes, including anxiety and memory impairment, as well as broader metabolic dysfunction.”

Velazquez leads the study as part of the ASU-Banner Neurodegenerative Disease Research Center, working with colleagues from the ASU School of Life Sciences, Banner Sun Health Research Institute and Mayo Clinic, AZ. The findings were published in Aging and Disease.

Obesity’s Early Impact on Brain Biology

Although obesity is widely known to increase the risk of chronic conditions such as heart disease and type 2 diabetes, this study suggests its influence on the brain may develop much earlier. The researchers measured elevated levels of inflammation-promoting proteins and enzymes that indicate liver stress. They also detected higher levels of neurofilament light chain (NfL), a protein released when neurons are damaged. NfL was linked to low blood choline levels in these young adults, even though no behavioral changes would typically be expected at this age.

NfL has emerged as an important early signal of neurodegeneration. It is found at elevated levels in people with mild cognitive impairment and Alzheimer’s disease. Observing these markers in young adults is significant and suggests that obesity may create measurable effects in the brain well before symptoms appear.

The results support the idea that inflammation, metabolic strain and early neuronal changes may be connected in a way that starts much earlier in life than once believed.

Choline’s Influence on Brain and Metabolic Health

A central aspect of the study involves choline, a nutrient essential for cell-membrane structure, inflammation control, liver function and the production of acetylcholine, a neurotransmitter important for memory. Participants with obesity had substantially lower levels of circulating choline, and these reductions corresponded with stronger signs of inflammation, insulin resistance, liver-enzyme elevation and NfL.

Although the liver produces some choline, most must come from food. Rich dietary sources include eggs, poultry, fish, beans and cruciferous vegetables such as broccoli, cauliflower and brussels sprouts. The researchers also observed that women in the study had lower choline levels than men, a notable finding because women experience higher rates of cognitive aging and Alzheimer’s disease.

National nutrition surveys show that many Americans do not meet recommended choline intake, especially teenagers and young adults. Since choline supports the brain and liver, long-term shortages may heighten vulnerability to metabolic stress and intensify the effect obesity has on the brain.

“Most people don’t realize they aren’t getting enough choline,” said Wendy Winslow, first co-author. “Adding choline-rich foods to your routine can help reduce inflammation and support both your body and brain as you age.”

Nutrient Considerations for New Weight-Loss Drugs

Modern weight-loss drugs have transformed obesity treatment because of their effectiveness in reducing weight and improving metabolic and cardiovascular health. However, the appetite-suppressing effects of GLP-1 medications significantly reduce food intake. This may lead to inadequate consumption of choline and other key nutrients. The authors note the need for future studies to explore whether pairing GLP-1 therapies with adequate dietary choline can help maintain metabolic resilience and overall health.

Study Design and Key Measurements

The research involved 30 adults in their 20s and 30s, split evenly between those with obesity and those of healthy weight. Each participant provided a fasting blood sample. The samples were analyzed for circulating choline, inflammatory cytokines, insulin, glucose, liver enzymes, additional metabolic measures and NfL.

Comparisons between groups revealed consistent patterns: lower choline levels, greater inflammation, metabolic stress and signs of neuronal damage in young adults with obesity. To understand how these findings relate to brain aging, the team compared their results with data from older adults diagnosed with mild cognitive impairment or Alzheimer’s disease.

The same pairing of low choline and high NfL was found in both young and older adults. This suggests that biological changes associated with Alzheimer’s may begin many years before symptoms arise, especially in people experiencing metabolic stress or obesity.

Early Indicators of Long-Term Cognitive Risk

Overall, the study highlights a strong link among obesity, inflammation, choline status and early neuronal stress. This combination may help explain why metabolic disorders increase the likelihood of cognitive decline later in life.

Although the study does not establish causation, it reveals a group of biomarkers that closely resemble those found in older adults with cognitive impairment. The results also align with earlier rodent studies showing that inadequate choline intake in mice can lead to obesity, metabolic problems and increased Alzheimer’s disease pathogenesis.

“Our results suggest that, in young adults, good metabolic health and adequate choline contribute to neuronal health, laying the groundwork for healthy aging,” says Jessica Judd, co-author of the study.

Ongoing research will continue exploring how early metabolic stress may shape long-term risk for neurodegenerative disease and could eventually inform new strategies to protect brain health across the lifespan.

The study was published on November 24 in JAMA Neurology and analyzed electronic health records from more than 11 million U.S. military veterans who received care through the Department of Veterans Affairs between 1999 and 2022.

Researchers from Oregon Health & Science University and the Portland VA Health Care System led the project.

Parkinson’s Risk Increases With Age

Parkinson’s is a progressive neurological disorder that affects an estimated 1 million people in the United States. The chance of developing the disease grows gradually each year after age 60.

The new research suggests that long-term, untreated sleep apnea may contribute to a higher risk of Parkinson’s.

Strong Association After Adjusting for Key Factors

Even after accounting for important contributors such as obesity, age and high blood pressure, the investigators still found a clear association between untreated sleep apnea and Parkinson’s disease. Among the millions of veterans with sleep apnea, those who did not use CPAP were nearly twice as likely to be diagnosed with Parkinson’s compared with individuals who used the therapy.

“It’s not at all a guarantee that you’re going to get Parkinson’s, but it significantly increases the chances,” said co-author Gregory Scott, M.D., Ph.D., assistant professor of pathology in the OHSU School of Medicine and a pathologist for at the VA Portland.

How Sleep Apnea Affects the Brain

Sleep apnea occurs when a person’s breathing repeatedly stops and restarts during sleep, which can keep the body from getting sufficient oxygen.

“If you stop breathing and oxygen is not at a normal level, your neurons are probably not functioning at a normal level either,” said lead author Lee Neilson, M.D., assistant professor of neurology at OHSU and a staff neurologist at the Portland VA. “Add that up night after night, year after year, and it may explain why fixing the problem by using CPAP may build in some resilience against neurodegenerative conditions, including Parkinson’s.”

Potential to Change Clinical Practice

Neilson said the results reinforce the importance of prioritizing sleep health for his patients, particularly in light of the elevated Parkinson’s risk revealed in the study.

“I think it will change my practice,” he said.

Veterans Report Clear Benefits From CPAP

Scott noted that some people with sleep apnea are hesitant to use CPAP, but he emphasized that many veterans have strongly positive experiences with the device.

“The veterans who use their CPAP love it,” he said. “They’re telling other people about it. They feel better, they’re less tired. Perhaps if others know about this reduction in risk of Parkinson’s disease, it will further convince peopel with sleep apnea to give CPAP a try.”

Study Contributors and Funding Support

In addition to Scott and Neilson, co-authors include Isabella Montano, B.A., Jasmin May, M.D., Ph.D., Jonathan Elliott, Ph.D., and Miranda Lim, M.D., Ph.D., of OHSU and the Portland VA Health Care System; and Yeilim Cho, M.D., and Jeffrey Iliff, Ph.D., of the University of Washington and the VA Puget Sound Health Care System.

The research received support from the VA through grant awards BX005760, CX00253, I01RX004822, I01RX005371, CX002022, BX006155 and Bx006155; the John and Tami Marick Family Foundation; the Collins Medical Trust; the National Institute on Aging of the National Institutes of Health, award P30AG066518; and the U.S. Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, Maryland 21702-5014, under award numbers HT9425-24-1-0774 and HT9425-24-1-0775. The authors note that the opinions, interpretations, conclusions and recommendations are their own and are not necessarily endorsed by the Department of Defense, the NIH, VA or other funders.

In earlier work, WPI-ICReDD scientists showed that a palladium catalyst paired with phosphine ligands could drive light-activated (reaction activated by shining light) transformations of aryl ketones, but the same system did not work for alkyl ketones. Their data indicated that alkyl ketyl radicals did form briefly. However, these radicals immediately returned an electron to the palladium center, a phenomenon known as back electron transfer (BET), before any useful reaction could proceed. As a result, the starting material remained unchanged.

Similar to traditional palladium-based catalysis, the behavior of photoexcited palladium catalysts is highly dependent on the phosphine ligand attached to the metal. The team suspected that choosing the correct ligand might unlock reactivity with alkyl ketones. The difficulty was scale: thousands of phosphine ligands exist, and experimentally screening them for an unfamiliar reaction would be slow, labor-intensive, and generate unnecessary chemical waste.

To overcome these limitations, the researchers turned to computational chemistry to narrow down the field of candidate ligands. They used the Virtual Ligand-Assisted Screening (VLAS) approach developed by Associate Professor Wataru Matsuoka and Professor Satoshi Maeda at WPI-ICReDD. Applying VLAS to 38 phosphine ligands, the method produced a heat map that predicted how well each ligand might promote the desired reactivity by analyzing electronic and steric properties.

Guided by these predictions, the team selected three ligands for laboratory testing and ultimately identified L4 as the most effective option — tris(4-methoxyphenyl)phosphine (P(p-OMe-C₆H₄)₃). This ligand successfully suppressed BET, allowing alkyl ketones to generate ketyl radicals and participate in high-yield transformations.

The resulting method provides chemists with an accessible way to work with alkyl ketyl radicals and demonstrates how VLAS can rapidly guide the development and optimization of new chemical reactions.

To better understand how ATP functions in this area, the team examined signaling patterns in the hippocampus and how they changed under stress. The hippocampus has long been associated with mood disorders, in part because it is sensitive to prolonged stress and is involved in shaping emotional behavior. disruptions in this region can affect how the brain processes stress, which may set the stage for depression or anxiety.

Stress, ATP Loss, and the Role of Connexin 43

The researchers found that male mice prone to developing depressive- and anxiety-like behaviors after long-term stress had lower levels of ATP. These mice also produced less of a key protein required for ATP release (connexin 43). Connexin 43 forms channels that allow ATP to move between certain cells, making it an important part of how the brain maintains healthy energy and signaling levels.

To test whether reduced ATP release contributed to mood-related symptoms, the team genetically decreased or removed connexin 43 in cells that normally release ATP. This experiment was done in another group of mice that had not been exposed to prolonged stress. Even without a stressful environment, lowering connexin 43 triggered depressive- and anxiety-like behaviors and reduced ATP levels. This finding suggested that disruptions in ATP release alone could influence emotional behavior.

When the researchers restored connexin 43 in the hippocampus of stressed mice, ATP levels returned to normal and the animals showed noticeable improvements in their behavior. This recovery helped reinforce the idea that ATP signaling plays a central role in regulating mood.

A Shared Biological Pathway for Depression and Anxiety

Gao explains, “This is the first direct evidence that deficient ATP release in [a region of the] hippocampus drives both depressive- and anxiety-like behaviors, revealing a shared molecular pathway [for these conditions].” Identifying such a pathway is important, as depression and anxiety often occur together and can be difficult to treat simultaneously with existing therapies.

Gao notes that the link between connexin 43 and ATP release highlights a possible target for future treatments. By improving or restoring ATP signaling, scientists may eventually be able to develop interventions that address both conditions at once. The research team also plans to include both male and female mice in upcoming studies to determine whether these mechanisms operate similarly across sexes, which could broaden the relevance of their findings.