BOSTON –Increasingly, Alzheimer’s disease (AD) research has focused on the preclinical stage, when people have biological evidence of AD but no or minimal symptoms, and when interventions might have the potential to prevent future decline of older adults. Researchers from Massachusetts General Hospital (MGH) have shed important new light on this area, reporting in a study published in JAMA Network Open that depression symptoms in cognitively healthy older individuals together with brain amyloid, a biological marker of AD, could trigger changes in memory and thinking over time.

“Our research found that even modest levels of brain amyloid deposition can impact the relationship between depression symptoms and cognitive abilities,” says Jennifer Gatchel, MD, PhD, of the MGH Division of Geriatric Psychiatry, and lead author of the study. “This raises the possibility that depression symptoms could be targets in clinical trials aimed at delaying the progression of Alzheimer’s disease. Further research is needed in this area”

Past research has shown an association between depression and cognitive deficits in older individuals. The MGH study, however, is among the first to reveal that this association is influenced by the presence of cortical amyloid in unimpaired older adults, even when depression symptoms are mild to moderate. Data were collected by researchers over a seven-year period from 276 community-dwelling older adults, all participants in the landmark Harvard Aging Brain Study (HABS). What they discovered was a significant link between worsening depression symptoms and declining cognition over two to seven years that was influenced by AD pathology, as measured by PET imaging of brain amyloid.

“Our findings offer evidence that in healthy older adults, depression symptoms together with brain amyloid may be associated with early changes in memory and in thinking,” explains Gatchel.  “Depression symptoms themselves may be among the early changes in the preclinical stages of dementia syndromes. Just as importantly, these stages represent a clinical window of opportunity for closely monitoring at-risk individuals, and for potentially introducing interventions to prevent or slow cognitive decline.”

MGH researchers also learned from their extensive work that not all older adults with depression symptoms and cortical amyloid will experience failing cognition. Other risk factors investigated by the authors that could modify the relationship between depression and cognition include brain metabolism and volume of the hippocampus, the part of the brain associated with learning and forming of new memories. The authors also note that other mechanisms, including tau-mediated neurodegeneration, hypertension, hypercortisolemia and inflammation, may be involved and need to be investigated.

“These findings underscore the fact that depression symptoms are multi-factorial and may actually work synergistically with amyloid and related processes to affect cognition over time in older adults,” notes Gatchel. “This is an area we will continue to actively study.”

Gatchel is assistant professor of Psychiatry at Harvard Medical School. Additional co-authors of the JAMA Network Open study include Gad Marshall, MD, Reisa Sperling, MD, and Keith Johnson, MD, Department of Neurology, Massachusetts General Hospital, and Deborah Blacker MD, ScD, Department of Psychiatry at Massachusetts General Hospital and Department of Epidemiology at the Harvard T.H. Chan School of Public Health. Support for the study includes National Institute on Aging (NIA) grants PO1 AGO36694, K24 AG035007, and K23 AG058805, the BrightFocus Foundation, the Alzheimer’s Association, and the Massachusetts General Hospital Rappaport Fellowship.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $925 million and comprises more than 8,500 researchers working across more than 30 institutes, centers and departments. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America’s Best Hospitals."