Temporal dynamics in the association between depression and dementia: an umbrella review and meta-analysis
Jacob Brain, Maha Alshahrani, Aysegul Humeyra Kafadar, Eugene Tang, Elissa Burton, Leanne Greene, Deborah Turnbull, Bronwyn Myers, Aliya Naheed, Mario Siervo, Phillip J. Tully, Blossom C. M. Stephan
Abstract
Background Identifying modifiable risk factors is crucial for dementia prevention, a global health concern. Depression is considered a risk factor for dementia, but the temporal dynamics across the life course remain inconclusive. Therefore, we aimed to systematically assess the relationship between the timing of depression assessment and risk of all-cause late-life dementia. Methods We conducted an umbrella review and meta-analysis to assess incident dementia in individuals with non-current history of depression. PubMed and Ovid Embase, MEDLINE, and PsycInfo were searched from inception up to February 17, 2025. Systematic reviews with meta-analyses investigating the association between depression and incident late-life dementia were included. From eligible reviews, we also extracted data from studies reporting dementia risk as hazard ratios (HRs), analysing the timing of depression measurement using random-effects models for meta-analysis. This study is registered with PROSPERO, CRD42021249706. Findings Of the 7763 records identified, nine reviews were eligible for inclusion of the umbrella review. One review was judged to be of moderate quality, while the others were either low ( n = 3) or critically low ( n = 5). For our meta-analyses, 18 studies reporting depression onset in later life ( n = 901,762 participants, n = 7595 incident dementia cases) and seven studies on depression assessed during midlife ( n ≥ 2,501,269 participants, n ≥ 276,929 incident dementia cases) were included. All studies in the meta-analyses were deemed to be of good quality, with no strong evidence of publication bias. Pooled HRs indicated depression present in late-life (HR 1.95, 95% CI: 1.68–2.26; I 2 = 77.5%) and midlife (HR 1.56, 95% CI: 1.12–2.18; I 2 = 97.5%) significantly increased risk of all-cause dementia. Interpretation The findings suggest that depression across the life course may increase dementia risk; however, substantial heterogeneity and review quality should be considered when interpreting the strength of this evidence. A life course approach to the treatment and prevention of depression may help reduce the burden of dementia, but this will require scaling up access to effective mental health care for vulnerable populations. Further research is needed to clarify if the stronger late-life association reflects depression as an immediate risk factor or an early manifestation of neurodegenerative processes. Funding National Institute for Health and Care Research, UK Research and Innovation, and Saudi Arabian Cultural Mission.