Specific midlife depressive symptoms and long-term dementia risk: a 23-year UK prospective cohort study.

内容摘要

Midlife depression has been associated with an increased risk of dementia, but it remains unclear whether this risk is attributable to specific symptoms. We aimed to identify the midlife depressive symptoms most strongly linked to subsequent dementia and to ascertain whether these associations were independent of established dementia risk factors. In this prospective, observational cohort study based on the UK Whitehall II study, participants (aged 35-55 years at study inception [1985-88]) were eligible for analysis if they had complete depression data and successful linkage to national health records; individuals with prevalent dementia at baseline were excluded. In 1997-99, the baseline for this analysis, participants underwent a clinical examination and completed the 30-item version of the General Health Questionnaire (GHQ-30, a validated screening instrument for detecting clinically significant psychiatric distress in the general population). Threshold-level depression was defined as a GHQ-30 score of 5 or higher. The primary outcome was incident dementia, ascertained via linkage to UK National Health Service (NHS) Hospital Episode Statistics for inpatient admissions, the Mental Health Services Data Set, or the NHS Central Registry for mortality from April 24, 1997, to March 1, 2023. Analyses were conducted using a series of multivariable-adjusted Cox proportional hazards regression models. Hazard ratios (HRs) and accompanying 95% CIs were adjusted for age, sex, and ethnicity in the basic model. People with lived experience were not involved in the study design or writing process. Of 6511 participants in the Whitehall II study who completed the GHQ-30 between April 24, 1997, and Jan 8, 1999, 5811 were eligible for this analysis. The mean age of participants was 55·7 years (SD 6·0; range 45-69); 1646 (28·3%) participants were women, 4165 (71·7%) were men, 5356 (92·2%) reported their ethnicity as White, and 455 (7·8%) reported their ethnicity as non-White. During a mean follow-up of 22·6 years (SD 5·0), 586 participants (10·1%) developed dementia. Six depressive symptoms emerged as robust midlife indicators of increased dementia risk: "Losing confidence in myself" (HR 1·51, 95% CI 1·16-1·96), "Not able to face up to problems" (1·49, 1·09-2·04), "Not feeling warmth and affection for others" (1·44, 1·06-1·95), "Nervous and strung-up all the time" (1·34, 1·03-1·72), "Not satisfied with the way tasks are carried out" (1·33, 1·05-1·69), and "Difficulties concentrating" (1·29, 1·01-1·65). Associations were independent of established dementia risk factors, including APOEε4 status, cardiometabolic conditions, and lifestyle factors. In individuals younger than 60 years at baseline, the six symptoms fully accounted for the association between midlife depression and dementia risk. A distinct set of midlife depressive symptoms was associated with an increased risk of dementia, suggesting that these symptoms might be early markers of underlying neurodegenerative processes. These findings could inform earlier identification and more targeted interventions for individuals with depression who are at risk of dementia. Wellcome Trust, UK Medical Research Council, National Institute on Aging, and Research Council of Finland.