Over 7 million people in the United States live with Alzheimer’s disease and related dementia (ADRD). Some risk factors for ADRD, like genetics, can’t be controlled, but others can be treated. One of the most prevalent is depression (known clinically as major depressive disorder, or MDD). Between 11.1% and 14.7% of ADRD cases – affecting roughly one million individuals in the US – are attributable to MDD.  

Now, researchers at the UConn Center on Aging have uncovered a variety of mechanisms linking these conditions, giving at-risk individuals and health care providers a greater understanding of how the disease may be prevented and mitigated. 

“We’ve known for a long time that depression is one of the most relevant, potentially preventable risk factors for Alzheimer’s disease,” says Breno Diniz, MD, Ph.D., associate professor of psychiatry at UConn Health and the Center on Aging, who has devoted his research career to tackling this issue. “However, we didn’t know why.”  

Diniz’s latest publication, in the journal Nature Mental Health, has uncovered two key factors linking these diseases: proteostasis, or how the body synthesizes and metabolizes proteins; and dysregulation of inflammatory responses.  

“Depression is a disease that is bigger than a depressed mood,” Diniz says. “It has consequences that are silent, that may appear many years later.” 

The Power in the Proteins

Diniz’s research team identified a series of protein markers in the body that seemed to increase the risk of ADRD for everyone – patients both with and without a history of MDD. These markers are related to general processes in the body that tend to change with age, such as inflammation, cell division, and apoptosis (the destruction and removal of damaged cells from the body). 

But in patients with MDD, the researchers found a unique change in the process of proteostasis. This change increased inflammation in the brain, which in turn increased the risk of developing ADRD. 

“What we have here is a causal effect,” says Diniz, explaining that these two factors – changes in proteostasis and an increase in neuroinflammation – “seem to work together, synergistically, to increase the risk of dementia.” 

Using this insight, the team developed a Proteomic Risk Score that can be used to assess the risk for an individual patient with depression developing ADRD. This unique tool evaluates multiple proteins and offers “a more concrete way of looking at the risk of dementia in these individuals,” says Diniz. 

To the research team’s surprise, the newly developed tool was a better predictor of ADRD risk than any previous model. It was more effective than models which evaluate the classic risk factors for ADRD, both in the general population and among those with depression – signaling hope for early detection and prevention. 

“It’s a very robust model,” says Diniz, “and it has concrete clinical applications.” 

The Proteomic Risk Score tool will help clinicians and patients holistically examine their ADRD risk factors, and it may also enable researchers to better select human subjects for ADRD intervention and prevention efforts. 

Breaking it Down

In this study, Diniz and his co-authors used a combination of proteomic and genomic approaches to analyze data available from the United Kingdom Biobank, specifically tracking ADRD outcomes among middle-aged adults with depression.  

Proteomics is the study of the proteins that are created by cells in the body. And genomics – the study of someone’s entire set of DNA – is a natural complement to proteomics, since DNA determines which proteins are produced by cells. Combining these two analytical approaches is called proteogenomics, and it can give researchers a deeper insight into complex biological processes and how they are related to different pathologies.  

“Every molecular layer – from genes to epigenetics, RNA, and proteins – conveys different biological information, and they can have different roles in … creating prediction models,” explains Diniz. “Their combination makes the models more powerful, and brings them a step closer to precision geroscience.” This is a major goal of the UConn Pepper Center, led by the paper’s co-authors George Kuchel, MD, and Richard Fortinsky, Ph.D.

To enable this multifaceted analysis, Diniz partnered with other researchers across departments at UConn and UConn Health, including Kuchel; Fortinsky; Zhiduo Chen, Ph.D.; David C. Steffens, MD; and Chia-Ling Kuo, Ph.D. The research team also included scientists from the University of Exeter (UK) and the Centre for Addiction and Mental Health in Toronto, Canada. 

Depression’s ‘Silent Consequences’

This research emphasizes the profound interconnection between mind and body, especially the long-term health impacts of untreated mental illness. For those outside the scientific community, Diniz hopes this work will spur people to take their mental health just as seriously as their 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 in the past decade have shown that any depressive episode throughout the lifespan, even in your 20s, can increase the risk of dementia later on. So, it’s very important to seek help, and it’s very important to treat – and try to reach full remission of – the depressive episode.” 

Fortunately, he notes, many of the lifestyle recommendations which have been shown to improve depressive symptoms – like exercise and not smoking – also improve other health outcomes, so treating depression does not need to occur in isolation. 

Offering patients and health care providers tools like the Proteomic Risk Score and a more holistic understanding of health, this research joins a growing body of literature dedicated to preventing many cases of ADRD before it’s too late. 

This work was supported by the NIA grant P30AG067988 (UConn Pepper Center, PIs: Kuchel and Fortinsky).