Dementia affects more than 57 million people globally, making it a significant public health concern. There is no definitive treatment currently available, but preventive therapies emphasize the recognition and management of modifiable risk factors such as depression. However, the influence of the timing of depression onset on its established association with increased dementia risk remains unclear. This study used an umbrella review and meta-analysis strategy to examine the temporal association between depression and the risk of all-cause late-life dementia.
A systematic literature search was conducted across PubMed, MEDLINE, and Embase databases, covering studies published up to February 17, 2025. This review focused on the relationship between depression and incident late-life dementia, including systematic reviews and meta-analyses.
The Newcastle–Ottawa Scale was used to evaluate the quality of individual studies that were part of the meta-analysis, while the AMSTAR 2 tool was used to evaluate the quality of the systematic reviews. Dementia risk was quantified using hazard ratios (HRs), which were pooled through random-effects models. The analysis was stratified by age at depression onset: midlife (18-64 years) and late-life (≥65 years). Effect estimates were standardized using the natural logarithm of the HRs (logHR) and their associated confidence intervals (CIs).
To evaluate the robustness of the results, sensitivity analyses were conducted using a leave-one-out approach and a separate meta-analysis using unadjusted HRs. Based on the ratio of one regression predictor per ten studies, and only univariable meta-regression models were used when the number of studies (k) was ≥ 10 articles.
Out of the 7763 screened articles, nine reviews were included in this umbrella review. The meta-analysis included 18 high-quality studies on late-life depression (n = 901,762 individuals, 7595 dementia cases) and seven on midlife depression (n >2.5 million participants, ≥276,929 dementia cases). Late-life depression was associated with nearly double the risk of all-cause dementia (HR 1.95, 95% CI: 1.68–2.26), whereas midlife depression was also associated with increased dementia risk, but to a lesser extent (HR 1.56, 95% CI: 1.12–2.18).
The association was strongest when depression occurred later in life, suggesting a potential prodromal role. Studies with shorter follow-up duration indicated a higher incidence of dementia, possibly reflecting early symptoms of dementia rather than a causal relationship.
In contrast, longer follow-up periods demonstrated weaker relationships. Meta-regression analysis explained 44.6% of this variability, supporting the hypothesis that late-life depression may function more as a prodrome than an independent risk factor. The umbrella review also revealed that most included reviews were rated as low or very low in quality, indicating the need for higher-quality evidence in this field.
Evaluation of mental and cognitive health throughout the life span must be combined in integrated care methods. This comprehensive analysis confirms that depression, whether occurring in midlife or later, is associated with an increased risk of dementia. A possible dual role as a prodromal indicator of dementia and as a modifiable risk factor is suggested by the higher relationship in later stages of life. Early detection and treatment of depression may therefore play a critical role in reducing the incidence of dementia and improving mental health outcomes in older adults.
Reference: Brain J, Alshahrani M, Kafadar AH, et al. Temporal dynamics in the association between depression and dementia: an umbrella review and meta-analysis. eClinicalMedicine. 2025;103266. doi:10.1016/j.eclinm.2025.103266
