Paris Alvar, Amirthalingam Guru, Karania Tasvee, Foote Isabelle F, Dobson Ruth, Noyce Alastair J, Marshall Charles R, Waters Sheena
Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado, USA.
J Neurol Neurosurg Psychiatry. 2025 May 14;96(6):573-581. doi: 10.1136/jnnp-2024-334675.
Depression is often cited as a major modifiable risk factor for dementia, though the relative contributions of a true causal relationship, reverse causality and confounding factors remain unclear. This study applied a subset of the Bradford Hill criteria for causation to depression and dementia including strength of effect, specificity, temporality, biological gradient and coherence.
A total of 491 557 participants in UK Biobank aged between 40 and 69 at enrolment and followed up for a mean duration of 12.4 years were studied. Diagnoses of depression and dementia were ascertained from linked health records, self-reports and death certificate registration. Depressive symptoms were measured at enrolment using a combination of questions based on the Patient Health Questionnaire-9 depression screening questionnaire. Regional grey matter volumes were measured using T1-weighted MRI in 41 929 participants.
Depression was a strong risk factor for incident dementia with an OR of 1.76 (95% CI 1.63 to 1.90), a relationship which was found to be specific to depression rather than commonly proposed confounders. Depressive symptoms increased rapidly in the 10 years prior to dementia diagnosis. The severity of depressive symptoms showed a dose-response relationship with dementia risk. Depression at older ages correlated with reduced grey matter volume in an Alzheimer's pattern whereas younger onset depression was associated with reduced grey matter volume in the frontal lobes and cerebellum.
This study provides evidence that the link between depression and dementia is due to reverse causation with a smaller component of causation with clear evidence of both mechanisms driving the association.
抑郁症常被认为是痴呆症的一个主要可改变风险因素，然而真正的因果关系、反向因果关系和混杂因素的相对作用仍不明确。本研究将布拉德福德·希尔因果关系标准的一个子集应用于抑郁症和痴呆症，包括效应强度、特异性、时间顺序、生物学梯度和连贯性。
对英国生物银行中491557名年龄在40至69岁之间的参与者进行了研究，这些参与者在入组时进行了平均12.4年的随访。抑郁症和痴呆症的诊断通过关联的健康记录、自我报告和死亡证明登记来确定。在入组时，使用基于患者健康问卷-9抑郁筛查问卷的问题组合来测量抑郁症状。在41929名参与者中，使用T1加权磁共振成像测量区域灰质体积。
抑郁症是新发痴呆症的一个强有力风险因素，比值比为1.76（95%置信区间为1.63至1.90），该关系被发现是抑郁症特有的，而非通常提出的混杂因素。在痴呆症诊断前的10年中，抑郁症状迅速增加。抑郁症状的严重程度与痴呆症风险呈剂量反应关系。老年抑郁症与阿尔茨海默病模式下的灰质体积减少相关，而早发性抑郁症与额叶和小脑的灰质体积减少相关。
本研究提供的证据表明，抑郁症与痴呆症之间的联系是由于反向因果关系，因果关系的成分较小，两种机制均有明确证据推动这种关联。
