Six depressive symptoms in midlife may pinpoint increased dementia risk

Six depressive symptoms in midlife are associated with an increased risk of dementia, a 23-year UK prospective cohort study has shown.

“Although midlife depression has been associated with an increased risk of dementia, it remains unclear whether this risk is attributable to specific symptoms,” wrote the researchers.

To identify the midlife depressive symptoms most strongly linked to subsequent dementia, the researchers conducted a prospective, observational cohort study involving 5,811 participants aged 45–69 years (mean age, 55.7 years; female, 28.3 percent; White, 92.2 percent) from the Whitehall II study. Midlife depressive symptoms were evaluated using the 30-item version of the General Health Questionnaire (GHQ-30) from 1997 to 1999. Participants with baseline dementia were excluded. The primary endpoint was incident dementia. [Lancet Psychiatry 2025;doi:10.1016/S2215-0366(25)00331-1]

“Our findings showed that dementia risk was linked to a handful of depressive symptoms rather than depression as a whole,” noted the lead author, Dr Philipp Frank of the Division of Psychiatry, University College London, London, UK.

After a mean follow-up of 22.6 years, 10.1 percent of participants developed dementia. Six depressive symptoms emerged as robust midlife indicators of increased risk of dementia:

•  Losing self-confidence (hazard ratio [HR], 1.51; 95 percent confidence interval [CI], 1.16–1.96);

• Not able to face up to problems (HR, 1.49; 95 percent CI, 1.09–2.04);
• Not feeling warmth and affection for others (HR, 1.44; 1.06–1.95);
• Nervous and strung-up all the time (HR, 1.34;1.03–1.72);
• Not satisfied with the way tasks are carried out (HR,1.33; 95 percent, 1.05–1.69);
• Difficulties concentrating (HR, 1.29; 95 percent CI, 1.01–1.65).

Age-specific dementia incidence rose gradually from midlife to older age, ranging from 0 cases per 1,000 person-years at ages <60 years to 39.0 cases per 1,000 person-years at ages 85–89 years, and to 66.7 cases per 1,000 person-years at ages ≥90 years. Of note, when stratified by baseline age group (<60 years vs ≥60 years), these increased risks were fully driven by individuals aged <60 years.

Additionally, associations were independent of established dementia risk factors, including APOEε4 status, cardiometabolic conditions, and lifestyle factors.

The 2024 Lancet Commission report on dementia prevention, intervention and care highlights depression as a potentially modifiable midlife risk factor. [Lancet 2024;404:572-628]

“Focusing on specific symptom patterns rather than treating depression as a single, unitary construct could improve early identification of individuals at increased risk of dementia and inform targeted prevention strategies,” pointed out the researchers.

“Further research should evaluate these findings in more diverse populations and investigate the biological and behavioural mechanisms linking specific symptom profiles to dementia,” they added.