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.

Se Chang Yoon, Ji Hyun An, Jung-Seok Choi, June Ho Chang, Yoo Jin Jang, Hong Jin Jeon. Clin Psychopharmacol Neurosci 2025;23:542-50. https://doi.org/10.9758/cpn.25.1346

This narrative review integrates longitudinal cohort studies, neuroimaging and biomarker research, and major clinical trials to examine how depression and cognitive decline interact across the dementia continuum. Depression and cognitive impairment frequently co-occur in late life and exhibit substantial clinical and biological overlap. Meta-analytic and large population-based cohort studies consistently show that late-life depression increases the risk of mild cognitive impairment and dementia, with stronger associations observed for vascular dementia than for Alzheimer’s disease. Neurobiological studies implicate cerebrovascular pathology, neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and fronto-subcortical circuit dysfunction as key mechanisms linking depressive symptoms to later cognitive decline. In a subset of older adults, new-onset depression—particularly when accompanied by executive dysfunction, subjective cognitive decline, or high white-matter hyperintensity burden—are associated with an increased likelihood of near-term cognitive decline and dementia, although evidence for a definitive prodromal state remains limited. Depression is also highly prevalent as part of the behavioral and psychological symptoms of dementia, occurring in 30–50% of individuals with Alzheimer’s disease and even higher proportions in dementia with Lewy bodies or frontotemporal dementia. Comorbid depression in dementia accelerates cognitive and functional decline, increases neuropsychiatric burden, and worsens quality of life for patients and caregivers. Therapeutically, antidepressant treatment may confer modest benefits on mood and selected cognitive domains (e.g., processing speed and executive function) in non-demented older adults, whereas in established dementia, antidepressant efficacy is limited. In contrast, cholinesterase inhibitors, memantine, and multimodal non-pharmacological interventions yield small but measurable improvements in depressive or apathy-related symptoms. Emerging disease-modifying therapies for Alzheimer’s disease have demonstrated cognitive benefits, but current trial data provide insufficient evidence regarding effects on depressive symptoms, highlighting an important gap for future research. These findings underscore the need for stage-specific, integrative strategies to address the intertwined trajectories of mood and cognition in aging.

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.

June Ho Chang, Yoo Jin Jang, Se Chang Yoon, Ji Hyun An, Jung-Seok Choi, Hong Jin Jeon. Clin Psychopharmacol Neurosci -0001;0:. https://doi.org/10.9758/cpn.25.1382