Introduction
Dementia is a major public health concern that affects more than 57 million people worldwide. Since there is currently no cure for dementia, it is essential to identify and address modifiable factors that can help reduce the risk, such as depression. Late-life onset depression has been associated with dementia in older adults (aged 65 years and older). However, recent evidence indicates that this risk may begin earlier than previously thought.
The relationship between depression and dementia is complex and may involve several factors. These include chronic inflammation, dysregulation of the hypothalamic-pituitary-adrenal axis, vascular changes, alterations in neurotrophic factors, and imbalances in neurotransmitters. Shared genetic factors and lifestyle changes may also contribute to the risk of developing these conditions. Midlife and later life may have different implications for dementia risk, with shorter intervals between episodes of depression and the onset of dementia potentially indicating early warning signs.
Previous meta-analyses and epidemiological studies have shown variability in the relationship between depression and the risk of developing dementia. This inconsistency may be due to differences in how depression and dementia are diagnosed, the populations studied, the duration of follow-up, and the consideration of factors that may influence the results, such as age, sex, and medication use.
Objective
This umbrella review and meta-analysis synthesise existing evidence on the relationship between depression and dementia.
Methods
An umbrella review and meta-analysis investigated incident dementia in individuals with a non-current history of depression. PubMed, Ovid Embase, MEDLINE, and PsycInfo were searched to February 2025. Systematic reviews with meta-analyses investigating the association between depression and the onset of late-life dementia were included. Data regarding dementia risk, reported as hazard ratios (HRs), were extracted from eligible reviews. The timing of depression measurements was analyzed using random-effects models for the meta-analysis.
Results
Out of 7,763 records identified, nine reviews were eligible for inclusion in the umbrella review. For the meta-analyses, 18 studies on depression onset in later life and seven studies assessing depression during midlife were included. All studies in the meta-analyses were considered good quality, with no strong evidence of publication bias. The pooled HRs indicated that depression present in late life and midlife significantly increased the risk of all-cause dementia.
Conclusions
This umbrella review and meta-analysis indicates that depression throughout life, particularly in older age, is associated with a higher risk of dementia. This suggests that depression may act as both an early warning sign and a modifiable risk factor. Thus, there is a need for targeted screening and management of depression in older adults. However, further research is necessary, particularly focused on earlier life stages, to understand how various factors, such as the impact of treatment, patterns of recurrence or remission, and the characteristics of depression over a lifetime (including the number of episodes, chronicity, and severity), influence dementia risk. While severity is likely significant, it was not adequately captured in this analysis. Additionally, studies conducted in low- and middle-income countries, as well as those outside North America and Europe, are crucial for creating effective global prevention strategies and ensuring broader representation in dementia research.
