Worsening Depression Points to Dementia Risk

Liam Davenport

May 04, 2016

Older adults with steadily increasing depressive symptoms may be at increased risk of developing dementia, Dutch investigators have discovered in findings that suggest that worsening depression may share a common etiology with dementia.

Investigators found that individuals aged 55 years or older who had had steadily worsening symptoms of depression, as revealed over several assessments, were almost 1.5 times more likely to develop dementia than those with a continuously low level of symptoms.

However, the population-based study did not reveal any association between depression and dementia risk in individuals with remitting depressive symptoms, the investigators, led by M. Arfan Ikram, MD, PhD, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands, note.

"This finding is consistent with the prodromal hypothesis, which suggests that depressive symptoms in older age possibly represent a prodrome or an early stage of dementia," the investigators write.

"Indeed, depressive symptoms might appear as a reaction to underlying subclinical cognitive impairment, and lie in a continuum between subclinical cognitive impairment and overt dementia," they add.

The study was published online April 29 in Lancet Psychiatry.

Shared Etiology

Investigators examined data on 3325 individuals from the ongoing, population-based Rotterdam Study of adults aged 55 years or older living in Rotterdam, the Netherlands.

The median age of participants was 74.88 years. They had undergone at least one assessment for depressive symptoms between 1993 and 2004 and were free of dementia at baseline.

The assessments, which included the Center for Epidemiology Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale–Depression, were used to model 11-year trajectories of depressive symptoms.

The team was able to identify five trajectories of depressive symptoms. The first model trajectory represented patients whose CES-D scores remained low (n = 2441, 73%); the second, patients whose CES-D scores were initially moderately high and then decreased (n = 369, 11%); the third, those whose scores were initially low, then increased, and then decreased (n = 170, 5%); the fourth, those with initially low scores that then increased steadily (n = 255, 8%); and the fifth, those whose scores were consistently high (n = 90, 3%).

During a period that comprised 26,330 person-years, 434 participants developed dementia, including 348 patients with Alzheimer's disease, 26 with vascular dementia, and 60 with other dementias.

Compared with the trajectory representing patients whose CES-D scores remained low, only those with steadily increasing scores had a significantly increased risk for dementia (hazard ratio [HR], 1.42; P = .024).

This remained the case after taking into account incident stroke (HR = 1.58; P = .041), after restricting the analysis to Alzheimer's disease as an outcome (HR = 1.44; P = .034), and after taking into account mortality as a competing risk (HR = 1.45; P = .019).

The increase in dementia risk associated with a trajectory of increasing depression scores was greater after the first 3 years of follow-up (HR, 1.45; P = .036). Adjusting for use of antidepressants reduced the observed dementia risk by approximately 10%.

Discussing the findings, Dr Ikram told Medscape Medical News that studying depression trajectories points to several important conclusions. The first concerns patients whose CES-D scores were initially low, then increased, and then decreased.

"There, we did not find any link with dementia at all, and our explanation there is that these might be people who have experienced a life event, maybe the loss of a partner or a disease, and they can't cope with that. Here, the depression is very clearly linked to this life event and has nothing to do with dementia," he said.

Dr Ikram believes that there are two likely explanations for the link between dementia risk and steadily increasing depressive symptoms.

"One is that factors that cause the depression are similar factors that cause dementia," he said. "What could these factors be?

"Theoretically speaking, it could be genetic factors, but also pathology that accumulates in the brain, especially pathology that affects vessels in the brain...not so much strokes but the subclinical accumulation of vascular damage in the brain," he added.

"That has been shown to be linked to dementia very strongly, even Alzheimer's, but there's also a body of literature showing that the same pathology also leads to depression.

"For me, it's a combination of two answers. One, the shared risk factors, and the second, that depression might be what we call prodrome, so the first manifestation of the disease process that will ultimately lead to dementia."

Whatever the explanation for the association, Dr Ikram feels that the findings point to the need for multiple assessments of depressive symptoms in elderly patients.

"What you see happening very often, not only in research but also in clinical practice, is that, especially in the elderly, just a single measurement is done," he said.

Although a clinician may think that an isolated occurrence of depression, as revealed in one assessment, is due to a life event, Dr Ikram said, a second measurement would reveal whether the person is recovering or has become chronically depressed.

Modifying Risk

In an accompanying editorial, Simone Reppermund, PhD, Department of Developmental Disability and Centre for Healthy Brain Ageing at the University of New South Wales, Sydney, Australia, says that although the current study offers insights into the relationship between depression and dementia risk, the question remains as to how the risk is modified.

"More studies of depression trajectories over a long period, with inclusion of biological measures, are necessary to understand the link between depression and dementia, in particular the underlying mechanisms," she writes.

"A focus on lifestyle factors such as physical activity and social networks, and biological risk factors such as vascular disease, neuroinflammation, high concentrations of stress hormones, and neuropathological changes, might bring new treatment and prevention strategies a step closer."

Dr Reppermund told Medscape Medical News that it is "often a challenge for health professionals to discover depression in the elderly, as symptoms between geriatric depression and dementia can overlap.

"Besides the mentioned memory problems, elderly people with depression often show behavioral changes, like avoidance of leaving the home or refusal to eat, and that also happens in dementia," she noted.

Although depressed patients, she said, are usually oriented to time, person, and place and typically complain and worry about memory problems, those with dementia are increasingly confused and disoriented and "often don't notice memory problems or don't seem to care.

"Researchers are still looking for the etiology of both depression and dementia, and it is likely that there is not one etiology but rather a combination of different risk factors (environmental and genetic) that lead to depression and dementia."

She described the vascular depression hypothesis as "only one possible link between depression and dementia. The most pressing question for me is, How can we prevent depression and dementia?

"Intervention programs, including physical activity, a healthy diet, and social stimulation, may help to reduce vascular disease, vascular depression, and dementia."

Funding was provided by the Erasmus Medical Center; ZonMw; the Netherlands Ministry of Education Culture and Science; and the Netherlands Ministry for Health, Welfare and Sports. The authors have disclosed no relevant financial relationships.

Lancet Psychiatry. Published online April 29, 2016. Abstract, Editorial

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