Association between pre-dementia psychiatric diagnoses and all-cause dementia is independent from polygenic dementia risks in the UK Biobank

Abstract

Background: Psychiatric disorders have been associated with higher risk for future dementia. Understanding how pre-dementia psychiatric disorders (PDPD) relate to established dementia genetic risks has implications for dementia prevention.

Methods: In this retrospective cohort study, we investigated the relationships between polygenic risk scores for Alzheimer's disease (AD PRS), PDPD, alcohol use disorder (AUD), and subsequent dementia in the UK Biobank (UKB) and tested whether the relationships are consistent with different causal models.

Findings: Among 502,408 participants, 9352 had dementia. As expected, AD PRS was associated with greater risk for dementia (odds ratio (OR) 1.62, 95% confidence interval (CI), 1.59-1.65). A total of 94,237 participants had PDPD, of whom 2.6% (n = 2519) developed subsequent dementia, compared to 1.7% (n = 6833) of 407,871 participants without PDPD. Accordingly, PDPD were associated with 73% greater risk of incident dementia (OR 1.73, 1.65-1.83). Among dementia subtypes, the risk increase was 1.5-fold for AD (n = 3365) (OR 1.46, 1.34-1.59) and 2-fold for vascular dementia (VaD, n = 1823) (OR 2.08, 1.87-2.32). Our data indicated that PDPD were neither a dementia prodrome nor a mediator for AD PRS. Shared factors for both PDPD and dementia likely substantially account for the observed association, while a causal role of PDPD in dementia could not be excluded. AUD could be one of the shared causes for PDPD and dementia.

Interpretation: Psychiatric diagnoses were associated with subsequent dementia in UKB participants, and the association is orthogonal to established dementia genetic risks. Investigating shared causes for psychiatric disorders and dementia would shed light on this dementia pathway.

Funding: US NIH (K08AG054727).

Keywords: Alcohol use disorder; Causal modelling; Dementia; Polygenic risks for dementia; Psychiatric disorders.

Fig. 1

Flowchart for the selection of the analysed participants from the UK Biobank cohort. ∗ ICD-10 F07–F09 diagnoses (n = 278) were set as missing, thus excluded from psychiatric as well as dementia diagnoses.

Fig. 2

Hypotheses on relationships between AD PRS and PDPD on Dementia. The graphical models are shown on the left side and the corresponding statistical models used for evaluation are on the right side. The graphical model a corresponds to three linear models for hypothesis a, wherein β₀, θ₀, φ₀ represent the intercepts of the regression models, and β₁, θ₁, φ₁ represent the regression coefficients. The error terms are denoted as ε₁, ε₂, and ε₃. An analogous notation is used for the linear models of hypothesis b, corresponding to the graphical model b, and hypothesis c, corresponding to both graphical models c and d. PRS: Polygenic risk scores for dementia; PDPD: pre-dementia psychiatric disorders including psychiatric diagnoses established before dementia diagnoses or psychiatric disorders without concurrent dementia diagnoses.