Identification of ethnicity-specific transcriptional regulators of Alzheimer's disease

Evidence suggests that ethnicity substantially impacts risk for Alzheimer’s disease, with elevated risk among Caribbean-Hispanics. However, the molecular manifestation of Alzheimer’s in this population has not been studied. IN collaboration with Dr. Giuseppe Tosto at Columbia University Medical Centre, we are performing the first RNA sequencing analysis of bulk brain tissue from over 40 Alzheimer’s disease and non-Alzheimer’s disease Caribbean Hispanics from upper Manhattan. We are further contrasting our results with those from an elderly cohort of 715 non-Hispanic Caucasians from Illinois. We are identifying those genes with sample-specific effects and performing gene enrichment analyses revealing biochemical pathways discordantly dysregulated in AD between Caribbean-Hispanics and Caucasian samples. This work provides molecular insight into a previously unstudied population and lays a foundation for targeted analyses and precision interventions aimed at these ancestrally divergent groups.

Genomic regulators of microglial function in human brain

Growing bodies of literature implicate the immune system in the development and progression of dementia due to Alzheimer’s disease. Previous work has identified genomic regulators of a brain cell type called microglia, which are essential for proper development, maintenance, and resilience of brain function. Follow-up work on this immune cell type and the putative genetic markers of its function will be essential to translate these discoveries to clinic. Unanswered questions include: A) Which genetic mutations are predictive of neuroinflammation, and B) Which fluid- and imaging-based biomarkers are specific to microglial activity? Key deliverables of this work include the corroboration of evidence that a common genetic mutation may serve as a robust marker of aberrant microglial function.

Integrative predictive modelling of risk and resilience to mental illness

Alleviating the burden of mental illness can be broadly approached in two ways: disease prevention and disease intervention. While the search for fundamental mechanisms of illness may yield cures targeting the roots of causal pathways, non-pharmacological modifiers of disease risk and severity could be equally useful and more practical; the cost of developing a novel drug for treatment of dementia in Canada is estimated at over $350 million, and all recent phase 3 clinical trials for Alzheimer’s disease drugs have failed to meet their primary endpoints. Interestingly, known modifiers of risk and resilience are often not accounted for. The primary goal of this work is to develop a predictive map of environmental and genomic factors that primary care clinicians and long-term caregivers alike can use to help guide best practices. Importantly, the discovery of modifiable behaviours associated with protection against illness can significantly boost public awareness and participation in preventative activities and programs.

Population-level cross-diagnostic analyses of Alzheimer's disease risk; interactions with epilepsy, glaucoma, and gingivitus

Mechanistic overlaps in age-associated pathologies are substantial and likely linked by common age-related processes. Chronic neuroinflammation, amyloid accumulation, and altered metabolic dynamics can influence multiple systems body-wide that ultimately result in similar neurological symptoms. We are exploring several hypotheses as part of intra- and inter-institutional collaborations, including: oral health and bacterial seeding of plaques in Alzheimer's disease, neurofibrillary tangle pathological cascades and glaucoma, and sub-clinical epileptiform activity and its relationship to sleep and implications for late life cognitive decline.