Six midlife symptoms of depression were tied to an increased risk of dementia, prospective research from the Whitehall II cohort showed.

Depressive symptoms that emerged as midlife indicators of increased dementia risk were:

• Losing confidence in oneself (HR 1.51, 95% CI 1.16-1.96)
• Not able to face up to problems (HR 1.49, 95% CI 1.09-2.04)
• Not feeling warmth and affection for others (HR 1.44, 95% CI 1.06-1.95)
• Feeling nervous and strung-up all the time (HR 1.34, 95% CI 1.03-1.72)
• Not satisfied with the way tasks are carried out (HR 1.33, 95% CI 1.05-1.69)
• Difficulties concentrating (HR 1.29, 95% CI 1.01-1.65)

These associations were independent of established dementia risk factors like APOE4 status, cardiometabolic conditions, and lifestyle factors, reported Philipp Frank, PhD, of University College London, and co-authors in Lancet Psychiatry.

“Not everyone with depression in midlife has a higher risk of developing dementia later in life. Instead, the increased risk appears to be driven by a small number of specific symptoms,” Frank told MedPage Today.

“Importantly, some of the most commonly seen symptoms in both our study and routine clinical practice — such as low mood or sleep disturbances — were not associated with increased dementia risk. Rather, the symptoms linked to dementia included loss of confidence, reduced ability to cope with problems, impaired social connections, and persistent nervousness,” he said.

“Clinically, this suggests that a more symptom-focused approach may help identify people with depression who are at greatest risk of dementia,” Frank pointed out.

“Several of the symptoms we identified, such as reduced problem-solving abilities, impaired social engagement, and loss of confidence, have clear anxiety-related features. Rather than fitting neatly into diagnostic categories, these symptoms likely reflect shared underlying processes, such as chronic stress or reduced cognitive and social engagement, which may be relevant for long-term dementia risk,” he added.

Depression is considered a modifiable risk factor for dementia. “Late-life depression is a long-established predictor of dementia, probably partly reflecting that depression can be an early sign of neurodegeneration,” observed Robert Stewart, MBChB, MSc, of King’s College London, and co-authors in an accompanying editorial.

This study is “an important step forward in understanding the association between midlife depression and dementia,” the editorialists wrote. “The findings considered here suggest that it might be preferable to move beyond depression as a single diagnostic category and instead consider a broader range of mood and anxiety symptoms.”

Two priorities emerged from these findings, they said. “First, we need to better understand how the identified midlife factors (loss of confidence, concentration difficulties, reduced problem-solving abilities, impaired social connections, and persistent nervousness) contribute to later dementia risk,” they noted. “Second, we must develop and test interventions to evaluate whether these factors are modifiable and whether addressing them can ultimately prevent or delay dementia.”

Frank and colleagues assessed data from 5,811 participants in the Whitehall II cohort, a British longitudinal study of civil service workers that began in 1985.

In 1997-1999, Whitehall II participants had a clinical exam and completed the 30-item version of the General Health Questionnaire (GHQ-30), a screening tool designed to detect psychological distress and mental well-being. Threshold-level depression was defined as a GHQ-30 score of 5 or higher.

Mean age at GHQ-30 screening was 55.7 years; 67.8% of participants were under age 60. Most participants (71.7%) were men and 92.2% were white.

Participants who were dementia-free at GHQ-30 screening were followed for 22.6 years. The primary outcome was incident dementia, ascertained by linking to health records until 2023.

During this period, 10.1% of participants developed dementia. Those classified as depressed in midlife (based on reporting five or more GHQ-30 symptoms) had a 27% higher risk of subsequently developing dementia (HR 1.27, 95% CI 1.03-1.56).

All correlations between symptoms and dementia were stronger in participants younger than 60 at GHQ-30 screening compared with those 60 and older. In those younger than 60, “the six symptoms fully accounted for the association between midlife depression and dementia risk,” the researchers noted.

The study had several limitations, Frank and colleagues acknowledged. “Our study was based on observational data, precluding the possibility of inferring causation,” they wrote.

“Our depression measure was based on self-report and limited to 30 items, which might not fully capture the breadth and severity of depressive symptoms,” they added.

In addition, the sample was made up of civil service employees who were mainly white, male workers.

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