Parkinson’s Disease Genetic Variants in Sporadic Early Onset Dementia: Results from the Longitudinal Early Onset Alzheimer’s Disease Study

Abstract

AbstractBackgroundMuch of the genetic etiology of sporadic early onset Alzheimer’s disease and frontotemporal dementia is largely unknown. Genetic investigation using whole exome sequencing (WES) data in the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) aims to address this gap, with the hypothesis that some individuals with early onset cognitive impairment may carry pathogenic, potentially causative variants in Parkinson’s disease (PD) genes.MethodsWhole exome sequencing data for cognitively impaired LEADS participants (N = 301) was processed using the GATK best practices pipeline with Sentieon software; joint‐called VCFs were annotated with Annovar, and the results were filtered to prioritize amino acid code‐altering variants with minor allele frequencies <1% that have not been reported as benign or likely benign in ClinVar. Variants in the acid beta‐glucocerebrosidase (GBA), leucine‐rich repeat kinase 2 (LRRK2), Parkin RBR E3 ubiquitin protein ligase (PRKN), PTEN‐induced putative kinase 1 (PINK1), protein kinase, interferon‐inducible double‐stranded rna‐dependent activator (PRKRA), and Parkinson disease 7, autosomal recessive early‐onset (PARK7) were reviewed. Heterozygous or homozygous carriers of variants meeting these criteria in GBA and LRRK2, as well as homozygous or potentially compound heterozygous variant carriers in the other genes, were reviewed for the presence of PD‐related symptoms documented with the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) collected at baseline (N = 283).ResultsThere were no variants meeting inclusion criteria for PINK1, PARK7, PRKN, or PRKRA. However, we observed 21 individuals with predicted or reported functional variant(s) in GBA or LRRK2. The mean screening visit age for these carriers was 59 (range 53‐64), and all but two were amyloid positive. While only one case was documented with motor symptoms, several participants had peripheral nervous symptoms such as neuropathy. 17 carriers had amnestic‐type dementia, with similar frequency to non‐carriers.ConclusionsWhile there are a small subset of individuals carrying functional variants in PD genes, they do not appear to substantially influence the phenotype of most cases at baseline. Future planned research efforts include assessing alpha synuclein pathology via alpha synuclein seeding assays, which will help clarify the potential role of mixed genetic etiology and pathology in risk for non‐familial early onset dementia.