Additive interaction of mid- to late-life depression and cerebrovascular disease on the risk of dementia: a nationwide population-based cohort study

Yoo Jin Jang, Cinoo Kang, Woojae Myung, Shinn Won Lim, Young Kyung Moon, Ho Kim, Doh Kwan Kim

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Background: Dementia is a progressive neurocognitive disease with a substantial social burden. No apparent breakthroughs in treatment options have emerged so far; thus, disease prevention is essential for at-risk populations. Depression and cerebrovascular disease (CVD) are independent risk factors for dementia, but no studies have examined their interaction effect on dementia risk. This study aimed to identify the association of depression and CVD with the risk of dementia and evaluate whether dementia risk among patients with comorbid depression and CVD is higher than the sum of the individual risk due to each condition. Methods: A population-based cohort study was conducted to analyze the Korean National Health Insurance Service-National Sample Cohort data of all individuals over 50 years of age. Individuals who had not been diagnosed with dementia at baseline were included and followed up from January 1, 2005, to December 31, 2013. A time-varying Cox proportional hazard regression model adjusted for potential confounding factors was used for the analysis. The interaction between depression and CVD was estimated based on the attributable proportion (AP), relative excess risk due to interaction (RERI), synergy index (SI), and multiplicative-scale interaction. Results: A total of 242,237 participants were included in the analytical sample, of which 12,735 (5.3%) developed dementia. Compared to that for participants without depression or CVD, the adjusted hazard ratio for the incidence of dementia for those with depression alone was 2.35 (95% confidence interval [CI] 2.21–2.49), CVD alone was 3.25 (95% CI 3.11–3.39), and comorbid depression and CVD was 5.02 (95% CI 4.66–5.42). The additive interaction between depression and CVD was statistically significant (AP—0.08, 95% CI 0.01–0.16; RERI—0.42, 95% CI 0.03–0.82; SI—1.12, 95% CI 1.01–1.24). The multiplicative interaction was significant too, but the effect was negative (0.66, 95% CI 0.60–0.73). Conclusions: In this population-based nationwide cohort with long-term follow-up, depression and CVD were associated with an increased risk of dementia, and their coexistence additively increased dementia risk more than the sum of the individual risks.

Original languageEnglish
Article number61
JournalAlzheimer's Research and Therapy
Issue number1
StatePublished - Dec 2021


  • Additive interaction
  • Alzheimer’s disease
  • Cerebrovascular disease
  • Cohort study
  • Dementia
  • Depression
  • Nationwide population
  • Risk factors


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