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.

Depression in late-life is linked to an increased risk of Alzheimer's dementia (AD), with the risk potentially varying according to the age at onset of depression. Previous studies have typically dichotomized depression onset ages between 55 and 65 years; however, the specific age at which depression onset increases AD risk in older adults remains unclear. In this study, we aimed to investigate the relationship between the age at onset of depression and AD risk, and compare the characteristics between different age groups. A longitudinal cohort of 251 older patients diagnosed with major depressive disorder was followed for up to 22 years. Participants were categorized into four groups based on depression onset age: ≤ 54 years, 55-64, 65-74, and ≥ 75 years. Annual cognitive assessments were conducted using the Korean Mini-Mental State Examination, with further neuropsychological testing when cognitive decline was suspected. Cox proportional hazards models were used to assess AD conversion risk across groups, adjusting for covariates. During follow-up ranging from 1.0 to 22.9 years, 75 patients (29.88%) converted to AD. Depression onset after age 75 years was significantly associated with a higher risk of AD conversion (hazard ratio [HR], 8.95; 95% confidence interval [CI], 3.41-23.48; p < 0.0001) and a shorter time to conversion compared to onset before age 55 (40.93 vs. 83.40 months). After adjusting for covariates, depression onset after age 75 remained significantly associated with AD conversion (adjusted HR, 5.20; 95% CI, 1.04-25.93; p = 0.0431). This group also had milder depressive symptoms and a higher prevalence of hypertension and cerebrovascular disease than those with depression onset before 55 years of age. The onset of depression after the age of 75 years was strongly associated with an increased risk of AD and a shorter time to dementia onset. Individuals with depression onset after age 75 appear more closely linked to vascular comorbidities, while those with depression onset before age 55 are characterized by severe and recurrent depressive episodes. The mechanisms underlying AD in individuals with depression may differ from those in individuals without prior depression.

Background and Objectives: While depression is associated with an increased risk of Alzheimer’s dementia (AD), traditional AD-related biomarkers, such as amyloid-beta, have shown limited predictive value for late-life depression. Oxidative stress has emerged as a potential indicator given its shared role in both depression and dementia. This study investigated the longitudinal relationship between oxidative stress biomarkers and risk of dementia in patients with depression. Materials and Methods: A longitudinal cohort of 146 older patients with major depressive disorder was analyzed. Biomarkers, such as nitrotyrosine, protein carbonyl, F2-isoprostanes, malondialdehyde, 4-hydroxynonenal, and 8-hydroxy-2′-deoxyguanosine, were collected at baseline and measured using an enzyme-linked immunosorbent assay. AD conversion was determined using comprehensive neuropsychological assessment. Cox proportional hazards models were used to evaluate the association between oxidative stress biomarkers and AD conversion after adjusting for confounders. The log-rank test, using the minimum p-value approach, was applied to determine the optimal cut-off value for significantly associated biomarkers of AD-free survival rates. Results: During the follow-up period ranging from 1.00 to 18.53 years, 41 (28.08%) patients converted to AD. Nitrotyrosine showed a significant association with increased risk of AD (adjusted hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.00–1.01; p = 0.0045). For clinical applicability, patients with plasma nitrotyrosine levels ≥170 nM as the cut-off value had a 5.14-fold increased risk of AD (adjusted HR, 5.14; 95% CI, 2.02–13.07; p = 0.0006). Other biomarkers, such as protein carbonyl, F2-isoprostanes, malondialdehyde, 4-hydroxynonenal, and 8-hydroxy-2′-deoxyguanosine, were not significantly associated with AD conversion. Conclusions: Nitrotyrosine, a biomarker that reflects nitrosative damage, emerged as a significant predictor of dementia risk in older patients with depression, highlighting its potential as an early biomarker of dementia. Further validation of these results is required using a larger sample size.

Inflammation has been postulated as a mediating factor in the development of Alzheimer’s disease (AD) pathology. We investigated candidate inflammatory markers related to conversion to AD among patients with depression. A longitudinal study was conducted with older women with depression who were at least 55 years of age, with a mean follow-up period of 5.73 years. At baseline, 9 inflammatory cytokines were measured using the immunoreactivity method. During follow-up, patients with depression who complained of cognitive impairment were evaluated and diagnosed with AD conversion. Association of the cytokines with conversion to AD was analyzed using multivariable Cox proportional hazards regression with adjusting covariates. For clinical applicability, the optimal cutoff value was determined using the minimum p value approach for the conversion to AD and was used to plot an AD-free survival curve. Among 132 participants, 34 patients with depression (25.76%) developed AD during their follow-up period. Higher levels of interleukin (IL) 1β at baseline (hazard ratio = 3.30 [95% CI, 1.11–9.78], p = .031) and lower levels of IL-10 (p < .001) were significantly associated with an increased risk of progression to AD. The survival curve plotted by the cutoff value of ≥0.25 pg/mL for IL-1β and ≤0.15 pg/mL for IL-10 suggested adjusted hazard ratios of 8.96 (95% CI, 3.48–23.09; p < .001) for IL-1β and 10.99 (p < .001) for IL-10, respectively. This study demonstrated that IL-1β and IL-10 were associated with conversion to AD among patients with late-life depression, suggesting their potential as predictive markers of the transition to AD from depression.