Having depressive symptoms speeds cognitive decline, but the relationship is not due to the presence of ²-amyloid, tau tangles, or other brain pathology, results of a new postmortem study suggest.
Researchers have known for some time that depression is related to elevated risk for mild cognitive impairment (MCI) and dementia, but they haven't agreed on why this is the case. Many in the field were convinced that the relationship is driven by underlying cognitive issues and that people become depressed as a result of getting more demented, researchers say.
This new study, however, puts that theory to rest, concludes lead author Robert S. Wilson, PhD, professor, neuropsychology, Departments of Neurological Sciences and Behavioral Sciences, Rush University Medical Center, Chicago, Illinois.
"The most reasonable conclusion from this study is that depression is a risk factor for cognitive decline, but that it does not work through the common pathologies that we associate with cognitive decline and dementia in old age, including amyloid plaques, tangles, Lewy bodies, strokes, and so on," Dr. Wilson told Medscape Medical News. "It's something else in the brain contributing to cognitive decline."
Although some past research has associated late-life depression with abnormalities in frontal-subcortical and limbic networks involved in emotional control, Dr. Wilson said that pinpointing the cause of the relationship between depression and dementia is still speculative. Dr. Robert S. Wilson
"That search will continue; figuring that relationship out will likely help us greatly in translating findings such as this into some sort of effective intervention," said Dr. Wilson. "In the meantime, we think that reducing depressive symptoms in older people might have a beneficial effect on cognition and this ought to be investigated."
The study was published online July 30 in Neurology.
Depressive Symptoms
Researchers used data from 2 cohort studies begun in the 1990s: the Religious Orders Study, which involved older Catholic clergy, and the Rush Memory and Aging Project, which recruited older lay individuals from the Chicago area. Participants completed yearly clinical assessments and agreed to a postmortem examination of their brain.
Annual examinations included a 10-item short form of the Center for Epidemiological Studies Depression Scale, which is similar to the original version of the scale, including the ability to capture change in symptoms over time, but doesn't incorporate cognitive symptoms. Participants also completed 18 cognitive tests at the annual visits.
The 1764 study participants included in the analysis had an average age of 76.6 years at the start of the study and an average of 16.2 years of schooling.
At baseline, each of these participants reported a mean of 1.0 symptom on the depression scale. In an analysis that assessed change in depressive symptoms during a mean of 7.8 years of follow-up, depressive symptoms increased over time, mainly because of a slight decline in the likelihood of having no symptoms.
Over the course of follow-up, 52.2% of the participants developed mild cognitive impairment (MCI). Incident MCI was associated with a higher level of depressive symptoms before MCI onset but not with rate of change in symptoms after MCI onset.
Just less than 18% of participants developed dementia during follow-up. Incident dementia was associated with a higher level of depressive symptoms before dementia onset and a slight decrease in symptoms thereafter.
Of the 680 participants who died during follow-up, a neuropathologic examination was completed on the first 582. At baseline, these participants reported a mean of 1.2 depressive symptoms. After adjustment for age at death, sex, and education, depressive symptoms slightly increased during a mean of 8.4 years of observation.
In these participants, the composite measure of ²-amyloid plaque burden ranged from 0 to 22.9 and the composite measure of tau tangle density ranged from 0 to 32.2. Also, 32.1% had at least 1 chronic gross infarct, 27.9% at least 1 chronic microinfarct, 12.1% had neocortical Lewy bodies, and 5.9% had hippocampal sclerosis.
The study found that severity of depressive symptoms, or change in symptoms over time, was not associated with any of these neuropathologic markers, all of which are known to be associated with dementia.
Continuous Outcomes
Since dementia develops by minute degrees, researchers looked at continuous outcomes. In a model looking at the interaction of neuropathologic markers with time, the markers together accounted for 31.8% of the variability in rates of cognitive decline.
When depressive symptoms and markers were included in the analysis, a higher level of depressive symptoms continued to be associated with a faster rate of cognitive decline. This higher level accounted for 4.4% of the residual variability in cognitive decline not attributed to neuropathologic burden.
Dr. Wilson noted that it's not just depression in older people but also depression in middle age that predicts later cognitive problems.
Along with his research colleagues, Dr. Wilson is reviewing some of the neuroimaging results from tests carried out during the annual visits and after death to see whether these shed any new light.
"One thing we can look at is the connectivity between brain regions," he said. "We can look for functional and structural changes that are associated with depression and its association with cognitive decline, so it helps us narrow down a little bit the areas and the kinds of abnormalities that might be present in the brain that might be driving this association."
A limitation of the research was that because participants were self-selected, the generalizability of the results is unclear. As well, measures of some disease processes, such as cerebrovascular disease, were incomplete, or, in the case of, for example, transactive response DNA-binding protein, weren't measured. In addition, some markers, such as hippocampal sclerosis, were infrequently observed.
Toxic Processes
For a comment on this study, Medscape Medical News approached Richard B. Lipton, MD, professor and vice chair, neurology, professor, epidemiology and population health, professor, psychiatry and behavioral science, and director, Division of Cognitive Aging and Dementia, Albert Einstein College of Medicine, Bronx, New York.
Dr. Lipton called the study "unique" in that its findings are inconsistent with the theory that depression is a manifestation of dementia-related brain pathology or that depression causes cognitive decline.
Instead, said Dr. Lipton, the findings support the hypothesis that late-life depressive symptoms, or factors accompanying depressive symptoms, independently contribute to cognitive decline.
"Treatment of depression may therefore represent a remediable risk factor for cognitive decline in older adults that is independent of the pathology of dementia," he said.
Also approached for comment, Meryl A. Butters, PhD, associate professor, psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, agreed that the study suggests some still unknown changes related to depressive symptoms probably enhance or accelerate cognitive decline.
"To me, this suggests not only that depressive symptoms are associated with toxic processes in the brain causing more rapid cognitive decline, but that as a research field, we should begin to investigate whether depressive symptoms — or major depression — in younger people have the same negative effect both in the brain and on cognitive decline once they reach older adulthood."
The implication of this, said Dr. Butters "is that not only may intervening quickly when older adults develop depression be important for cognitive health, but that ultimately this may apply to younger people as well."
But Dr. Butters said caution is in order when interpreting the results of the study because it didn't include information about participants' psychiatric history. It's "highly likely" that some participants had a history of major depression or generalized anxiety disorder as these are the most common mental disorders, she said.
"These could be influencing either the levels of pathologic changes in the brain and/or rate of cognitive decline, far more than the depressive symptoms in old age measured in the study."
In addition, said Dr. Butters, in the overall sample, the level of depressive symptoms was quite low, with most having no symptoms. "Only a tiny percent had high enough depressive burden or symptoms that a mental health professional would consider substantial."
Dr. Butters added that at 4.4%, the amount of cognitive decline accounted for by depressive symptoms was "rather modest."
The study was funded by the National Institute on Aging and the Illinois Department of Public Health. Dr. Wilson serves as a consulting editor for Aging, Neuropsychology and Cognition, Psychology and Aging, and Neuropsychology, has served as a consultant for Pain Therapeutics Inc, and receives research support from NIH and Alzheimer's Association.
Neurology. Published online July 30, 2014. Abstract
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Poster Comment:
a slight decrease in (depressive) symptoms thereafter. Probably due to forgetting what they were depressed about.