Polygenic risk for dementia with Lewy bodies

Dementia with Lewy Bodies (DLB) is an understudied Alzheimer’s-related dementia characterized neuropathologically by the accumulation of Lewy bodies in the brain. Like other dementias, definitive diagnosis can only be made upon autopsy after death, though numerous clinical features such as visual hallucinations, Parkinsonism, and REM sleep behavior disorder are associated with the condition. DLB is thought to account for approximately 5% of dementia diagnoses. A major barrier to understanding the natural history and pathology of this condition is the lack of definitive diagnoses that can be made during a patient’s lifetime.

Recently, a polygenic risk score (PRS) was developed that can help identify people at higher risk of developing DLB based on their genetic profile (Chia et al, 2021). Intriguingly, the genetic variants associated with DLB identified in this study are also associated with risk of either Alzheimer’s disease or Parkinson’s disease, consistent with other observations that have identified pathological features in DLB similar to those two.

This study will examine the association of the DLB polygenic risk score with various phenotypic measures in the ADSP. The goal of this analysis is to determine if specific features are enriched in people with a high propensity for DLB based on genetics. To the extent that these people have another diagnosed dementia, this would suggest the possibility of a misdiagnosis. Specifically, we will examine individuals whose data is shared through the NIA’s NIAGADS Data Sharing Service.

For each individual, we will compute the DLB PRS previously described [3]. We will then ask if the score correlates with a diagnosis of Alzheimer’s disease, presence of amyloid, Braak stage, or Parkinson’s Disease Braak stage. We will also look at subsets of the DLB PRS consisting only of SNPs associated with Alzheimer’s disease or Parkinson’s disease.

Dementia with Lewy bodies (DLB) is an understudied dementia with features similar to both Alzheimer’s disease and Parkinson’s disease. Recent studies have developed a polygenic risk score that can predict who is at higher risk of DLB on the basis of their genetics. Genetic factors in this score have also been associated with Alzheimer’s disease and Parkinson’s disease. Here we will ask how the DLB risk score correlates with Alzheimer’s diagnosis and various features of the brains of people with Alzheimer’s to better understand the relationship between DLB, Alzheimer’s, and Parkinson’s.