Six specific depressive symptoms experienced during midlife may predict the risk for dementia more than two decades later.

In a cohort study of nearly 6000 middle-aged adults, several symptoms were robustly associated with an increased risk for dementia after 23 years of follow-up, including reduced self-confidence, avoidance of problems, lack of warmth or affection toward others, difficulty concentrating, persistent nervousness, and dissatisfaction with task performance.

These associations were largely independent of known dementia risk factors, such as APOE epsilon 4 status and lifestyle.

“Our findings show that dementia risk is linked to a handful of depressive symptoms rather than depression as a whole,” lead study author Philipp Frank, PhD, Division of Psychiatry, Faculty of Brain Sciences at University College London (UCL) in London, England, said in a release.

“This symptom-level approach gives us a much clearer picture of who may be more vulnerable decades before dementia develops,” Frank added.

The findings were published online on December 15 in The Lancet Psychiatry.

Novel Research

Previous research has shown a link between midlife depression and increased dementia,but the current investigators wanted to explore whether specific depression symptoms might contribute to risk.

The prospective, observational cohort study assessed data from 5811 adult participants in the UK Whitehall II study (mean age, 55.7 years; 72% men; 92% White).

Between 1997 and 1999 (baseline), all participants completed the 30-item General Health Questionnaire (GHQ-30) and underwent a clinical exam. A GHQ-30 score of 5 or higher was considered to be the threshold for depression (n = 1248). The primary outcome was incident dementia, determined by inpatient admissions, the Mental Health Services Data Set, or a National Health Service registry.

After a mean of 22.6 years, 10% of the participants developed dementia. Meeting the threshold for depression was associated with a significantly increased risk for dementia (hazard ratio [HR], 1.27).

Significant midlife indicators for subsequent dementia risk were “losing confidence in myself” and “not able to face up to problems” (HRs for both, 1.5); “not feeling warmth and affection for others” (HR, 1.4); and “nervous and strung-up all the time,” “not satisfied with the way tasks are carried out,” and “difficulties concentrating” (HRs for all, 1.3).

All symptom-dementia associations were stronger among participants younger than 60 years at baseline (mean age, 52 years) than among older participants (mean age, 63.2 years).

In further analyses, excluding participants with any of these specific symptoms attenuated the association between depression and dementia, reducing HR from 1.27 to 0.77.

The overall findings suggest that “these symptoms might be early markers of underlying neurodegenerative processes,” the investigators wrote.

“This is a new and important way of considering depression and dementia, and it is more evidence that depression is a wide umbrella and not necessarily one illness,” study author Gill Livingston, Division of Psychiatry at UCL in London, England, and chair of the Lancet Commission on dementia prevention, said in the release.

Frank added that paying attention to these patterns “could open new opportunities for early prevention.”

An Opportunity for Prevention?

In an accompanying editorial, Beatriz Pozuelo Moyano, Department of Psychiatry at Lausanne University Hospital in Lausanne, Switzerland, and colleagues applauded the focus on depressive symptoms rather than diagnoses, describing the research as “an important step forward” in understanding the association with dementia.

“The particular cluster of depressive symptoms identified by Frank and colleagues…seems obvious markers of both preceding and subsequent mental stress,” they wrote.

They added that further studies are needed to assess how midlife stress evolves later in life.

“The midlife-to-late-midlife period could be a key preventive window during which achievable lifestyle changes could help maintain cognitive reserve and reduce subsequent dementia risk,” the editorialists wrote.

The study was funded by the Wellcome Trust, the Research Council of Finland, the UK Medical Research Council, and the US National Institute on Aging. The investigators reported no relevant financial relationships. The editorialists reported being members of the European Task Force for Treatment-Resistant Depression in Older People. Pozuelo Moyano reported participating in an expert consultancy meeting organized by Lundbeck.