Researchers at the University of Connecticut (UConn) Center on Aging have uncovered new risk factors that link depression to Alzheimer’s disease and related dementia (ADRD). This discovery could significantly impact how at-risk individuals and healthcare providers approach prevention and treatment. Currently, over 7 million people in the United States live with ADRD, with depression identified as a major contributing factor.
According to the study, between 11.1% and 14.7% of ADRD cases in the U.S.—affecting approximately one million individuals—are attributable to major depressive disorder (MDD). The findings, published in the journal Nature Mental Health, reveal key mechanisms that connect these conditions, offering hope for more effective interventions.
Uncovering the Mechanisms
Dr. Breno Diniz, an associate professor of psychiatry at UConn Health, has long focused his research on the link between depression and Alzheimer’s. “We’ve known for a long time that depression is one of the most relevant, potentially preventable risk factors for Alzheimer’s disease,” Diniz states. “However, we didn’t know why.”
Diniz’s latest research identifies two critical factors: proteostasis, which involves the body’s synthesis and metabolism of proteins, and the dysregulation of inflammatory responses. “Depression is a disease that is bigger than a depressed mood,” Diniz explains. “It has consequences that are silent, that may appear many years later.”
The Role of Proteins
The research team discovered a series of protein markers that increase ADRD risk in both patients with and without a history of MDD. These markers are related to aging processes such as inflammation, cell division, and apoptosis. In patients with MDD, a unique change in proteostasis was observed, leading to increased brain inflammation and a higher risk of developing ADRD.
“What we have here is a causal effect,” says Diniz, noting that changes in proteostasis and increased neuroinflammation “seem to work together, synergistically, to increase the risk of dementia.”
Using these insights, the team developed a Proteomic Risk Score to assess the risk of ADRD in individuals with depression. This tool evaluates multiple proteins, providing a more concrete assessment of dementia risk in these individuals.
Advancements in Risk Prediction
The Proteomic Risk Score has proven to be a better predictor of ADRD risk than previous models, offering hope for early detection and prevention. “It’s a very robust model,” Diniz remarks, emphasizing its practical clinical applications.
This tool allows clinicians and patients to examine ADRD risk factors holistically and may help researchers select human subjects for ADRD intervention and prevention efforts.
Methodology and Collaboration
Diniz and his co-authors employed proteomic and genomic approaches to analyze data from the United Kingdom Biobank, focusing on ADRD outcomes among middle-aged adults with depression. Proteogenomics, the combination of proteomics and genomics, provided deeper insights into complex biological processes related to these pathologies.
“Every molecular layer—from genes to epigenetics, RNA, and proteins—conveys different biological information,” Diniz explains. “Their combination makes the models more powerful, and brings them a step closer to precision geroscience.”
The research involved collaboration with experts across UConn and UConn Health, as well as scientists from the University of Exeter and the Centre for Addiction and Mental Health in Toronto.
Implications for Mental Health
This research underscores the profound connection between mind and body, highlighting the long-term health impacts of untreated mental illness. Diniz hopes the findings will encourage individuals to prioritize mental health as much as physical health.
“It’s extremely important to seek help,” Diniz urges. “Not only when you’re 50 or older—anytime in your life. Lots of studies have shown that any depressive episode throughout the lifespan can increase the risk of dementia later on.”
Fortunately, lifestyle changes that improve depressive symptoms, such as exercise and smoking cessation, also enhance other health outcomes. This research, supported by the NIA grant P30AG067988, contributes to a growing body of literature aimed at preventing ADRD before it becomes too late.
