Identifying genetic variants associated with multiple pathologic changes in Alzheimer’s Disease and Related Dementias

Multiple pathologic changes are common in old age and are associated with dementia. While Alzheimer’s disease neuropathologic changes (ADNC) remain the most common pathology observed in older adults, there is also wide recognition for the role of cerebrovascular neuropathologic changes, Lewy body pathology, TAR DNA-binding protein 43 (TDP-43), hippocampal sclerosis in age-related cognitive decline. These pathologies often do not exist in isolation and individuals harboring multiple types of pathologies are found to have worse clinical outcomes compared to individuals with any one specific pathology. The genetic mechanisms and risk factors of the presence of multiple pathologies however are not well understood. While studies have shown shared risk alleles across various pathologies, it remains unclear how multiple pathologies are linked and why individuals with any one pathology develop comorbid pathologies while others do not. Identification of genetic variants distinct and shared between each pathology will highlight potential mechanistic links and dissect differences across pathologic changes. The goal of the planned analyses is to identify genetic variants associated with comorbid pathologies and to assess the relationships in genomic and RNA-level information with clinical outcomes across multiple pathologies. We will use integrated clinical, neuropathologic, and sequencing data from the ADSP-PHC and the 90+ study to 1) identify new and previously identified risk alleles associated with neuropathologic changes and 2) relate genomic information with transcriptomic data from publicly available RNA sequencing datasets, and 3) determine the associations between the genomic and transcriptomic information to clinical outcomes (cognitive, motor, and neuropsychiatric symptoms) across different pathologic changes. We will perform separate analyses on the ADSP-PHC and 90+ study datasets. All analyses will be adjusted for age at death, sex, and ethnicity.  

With advancing age, the presence of multiple brain pathologies is common and associated with dementia. While Alzheimer’s disease is the most common pathology observed in older adults, other changes like cerebrovascular pathology, Lewy body pathology, TDP-43 pathology, and hippocampal sclerosis also play a role in cognitive decline. People with multiple types of brain changes tend to have worse outcomes. Understanding why some individuals develop multiple pathologies while others don't is still not clear, but genetics may provide some insight into mechanisms underlying and linking multiple pathologies. By studying genetic variants associated with these brain changes and their impact on clinical outcomes, we aim to uncover new insights. Our research, using data from the ADSP-PHC and the 90+ study, will explore these connections and help shed light on the complex interplay between genetics, brain changes, and functional decline.