Unraveling the Complexities of Dementia: Insights from Our R21 Grant

Dementia, affecting around 50 million people globally, poses a significant health burden. Among its various forms, Alzheimer’s disease (AD) is the most prevalent, marked by the abnormal accumulation of amyloid beta (Aβ) and tau proteins in the brain. Following AD, dementia with Lewy bodies (DLB) is another common form, characterized by α-synuclein protein (α-syn) neuronal inclusions. Interestingly, neuropathology studies have revealed that many dementia patients exhibit mixed pathologies, where multiple underlying conditions contribute to the syndrome. This complexity underscores the need for a deeper understanding of how these pathologies interact to drive neurodegeneration and cognitive decline.

Our R21 grant from the National Institute on Aging (NIA) supports a groundbreaking clinical translational study aimed at dissecting these intricate relationships. Utilizing advanced systems biology and proteomics techniques, we are investigating the differentially expressed genes and proteins in patients with AD, DLB, and mixed dementia pathologies. Our goal is to determine whether certain brains are more susceptible to developing mixed pathologies involving both Aβ and α-syn. Previous research suggests that dysregulation of endosomal-lysosomal pathways may play a crucial role in these conditions. However, the challenge has been to isolate the effects of these pathways in mixed versus singular pathologies.

To address this, we are conducting a comprehensive proteomic and transcriptomic analysis of brain, cerebrospinal fluid (CSF), and plasma samples from three patient groups (AD, DLB, and mixed AD-DLB) and comparing them with age and sex-matched normal controls. By validating our findings against large national datasets such as ADNI and the Accelerating Medicines Partnership-AD, we aim to develop a model that elucidates the role of vesicular transport protein dysregulation in mixed pathologies. If our hypothesis holds true, this research could pave the way for targeted therapeutic strategies for mixed pathology dementia. Even if the hypothesis is disproven, our study will significantly advance our understanding of the proteomic and transcriptomic variability in neurodegenerative diseases, offering valuable insights for future research and clinical applications.