The relationship between psychiatric disorders and known genetic risks of dementia

By Neha MathurFeb 8 2024Reviewed by Danielle Ellis, B.Sc.

In a recent study published in eBioMedicine, researchers investigated how pre-dementia psychiatric diagnoses relate to well-recognized genetic risk factors for dementia in a large longitudinal population-based cohort—the United Kingdom Biobank (UKB).

They combined pre-dementia psychiatric disorders (PDPD), such as alcohol use disorder (AUD) and Alzheimer's disease (AD), as a single variable as they have overlapping genetic architectures, which helped them explore whether these were independently causal for dementia or have shared causes with dementia.

Background

Several population-based cohort studies have found that schizophrenia and depression increase the risk for dementia. 

Moreover, genome-wide association studies (GWAS) have identified 75 independent genomic risk loci, which capture around 50% of the heritability of dementia syndromes, such as Alzheimer's disease-related dementias (ADRD). Studies have not yet investigated how psychiatric disorders relate to known genetic risk factors for dementia. 

Each common genetic variant exerts little effect on dementia risk, which aggregates to polygenic risk scores (PRS) when their effects are combined. Since PRS captures a relevant share of total heritability, it may help identify individuals at higher risk of subsequent dementia. An understanding of these associations can inform strategies for dementia prevention and treatment.

About the study

In the present study, researchers enrolled UKB participants aged 37-69 to examine the risk of age-related mental diseases due to the complex interplay of genetic, lifestyle, and environmental factors. They obtained diagnosis codes and years of diagnosis from multiple sources to specifically analyze PDPD and dementia.

The researchers applied four graphical causal models to test their hypotheses that PDPD signifies mild behavioral impairment (MBI), or it mediates the effect of genetic risks on dementia, or PDPD is independent of the known genetic dementia risk factors, and finally, are there any other shared causes of the association between PDPD and dementia. 

PRS for 53 diseases and quantitative traits were normalized to a mean of zero and a standard deviation (SD) of one and used in a multivariable logistic regression analysis to estimate the association between PDPD and dementia, adjusted for various factors.

The primary outcome was diagnoses of AD, vascular dementia (VaD), and unspecified dementia, for which they obtained PRSs. The models also explored reverse causation, PDPD's mediating effect on AD PRS and dementia, the collider effect between PDPD, dementia, and PRS, and the role of shared risk factors like AUD.

Results

The analysis set had data from 502,408 UKB participants (54.4% females) with an average age of 56.5 years at recruitment. Among them, 18.8% had PDPD, of which 2.6% developed dementia, while 1.7% of those without PDPD also developed dementia. 

Even having one PDPD increased the likelihood of subsequent dementia by 73% in 12–16 years (short-term). Even though less common, psychotic and bipolar spectrum disorders were also associated with a greater dementia risk.

In univariate regression analysis, PRS and PDPD were associated with greater risk for subsequent dementia, with a respective odds ratio (ORs) of 1.58 and 1.61, 95% CI, and this association remained significant even after adjusting for gender, age at recruitment, educational and smoking status, AUD, and PCs. 

Intriguingly, PRS was associated with an increased risk of all-cause dementia and its subtypes and remained unchanged even when the analysis encompassed participants of European ancestry only.

Causal modeling revealed that shared causes for PDPD and dementia mainly accounted for the association between them, and PDPD alone only played a small causal role in dementia. Results also showed that PDPD in <40-year-olds increased risk for dementia more than late-life PDPD, i.e., in people >60-year-olds, which nullifies the reverse causation theory that psychiatric disorders signify prodromal dementia. 

Further, the study models indicated AUD as a shared risk factor for both PDPD and dementia (ORs=3.30, 4.42; 95% CI), while the association between PDPD and incident dementia was independent of the dementia polygenic risk. 

Conclusion

Overall, this retrospective cohort study found that PDPD was associated with a 73% greater risk of incident dementia, with a 1.5- and two-fold increase for AD and VaD, respectively.

The association between psychiatric diagnoses and subsequent dementia was orthogonal to established dementia genetic risks, suggesting AUD could be one of the shared causes of PDPD and dementia. These shared, modifiable risk factors account for a large part of the association between psychiatric disorders and dementia. 

Further investigating the shared causes of psychiatric disorders and dementia may help design appropriate dementia interventions.