Polygenic risk for psychiatric disorders and its association with neuropsychiatric symptoms in dementia.

Researchers studied whether having genes linked to mental health conditions affects behavior problems in people with dementia. They looked at over 7,000 people with different types of dementia. Surprisingly, they found that people with frontotemporal dementia who had genes linked to schizophrenia actually had fewer behavior problems. This finding was unexpected and needs more research to understand why this happens.

This large-scale genetic study examined whether polygenic risk scores for psychiatric disorders (major depression, schizophrenia, bipolar disorder, and autism) are associated with neuropsychiatric symptoms in dementia. Researchers analyzed genetic and clinical data from 7,058 patients with Alzheimer's disease, frontotemporal dementia (FTD), or dementia with Lewy bodies across five European cohorts. The study found that higher genetic risk for schizophrenia was unexpectedly associated with lower neuropsychiatric symptoms in FTD patients, but no associations were found in other dementia types. This represents the first evidence linking psychiatric genetic liability to symptom presentation in dementia, though the finding requires further investigation to understand the underlying mechanisms.

Findings suggest genetic factors may influence neuropsychiatric symptom expression differently across dementia types. The unexpected protective association in FTD warrants further investigation and may eventually inform personalized approaches to managing behavioral symptoms in dementia.

This is the first study of its kind, so findings require replication. The counterintuitive finding of protective effects needs mechanistic explanation. Sample sizes varied between dementia types, and the study design cannot establish causality.

Neuropsychiatric symptoms are common in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), yet their genetic underpinnings remain unclear. To gain insight into biological processes related to neuropsychiatric symptoms in dementia, we investigated whether polygenic risk scores (PRS) for psychiatric disorders - major depressive disorder (MDD), schizophrenia (SCZ), bipolar disorder (BD), and autism spectrum disorder (ASD) - are associated with neuropsychiatric symptoms in dementia. Data included genetic and neuropsychiatric data of 6240 AD patients, 428 FTD patients and 390 DLB patients from five European cohorts (ADC, GR@ACE, DELCODE, AgeCoDe, and DCN). PRS for MDD, BD, SCZ, and ASD were calculated using LDpred2.

Neuropsychiatric symptoms were assessed using total scores from the Neuropsychiatric Inventory (NPI) (NPI-12 and NPI-Q) and Geriatric Depression scale (GDS). Associations between PRS and symptoms were examined using linear regression models, followed by meta-analyses. In FTD, higher SCZ-PRS associated with lower NPI scores in the meta-analysis (β = -0.12, = .001). No associations were found in AD and DLB.

This is the first study to show that genetic liability for SCZ associates with lower NPI in FTD, warranting further investigation.