EP 237: How genetics and environment shape neurodegeneration in Alzheimer's and Parkinson's with Sarah Marzi of King’s College London

This week on The Genetics Podcast, Patrick is joined by Dr. Sarah Marzi, Senior Lecturer at King's College London and group leader at the UK Dementia Research Institute. They discuss the impact of genes and environment on neurodegenerative disease, including: how APOE genotype shapes microglial function, how cell type-specific epigenomics of postmortem brain tissue is revealing the role of microglia and oligodendrocytes in Alzheimer's disease, and how pesticide exposure drives selective dopaminergic neuron loss and neuroinflammation in Parkinson's.

Show Notes

0:00 Intro to The Genetics Podcast

00:59 Welcome to Sarah

02:13 Environmental contributions to Parkinson’s disease and ALS

05:01 The role of microglia in Alzheimer’s disease and findings from a study on APOE variants in a mouse model

12:50 APOE4 effects on lipid accumulation, microglial activation, and vitamin D receptor signaling 

14:20 Building a multi-omic atlas of the Alzheimer’s brain

18:01 Overview of the pathological cascade of events in the Alzheimer’s brain

20:31 Anti-amyloid therapies, early intervention, and combination treatment strategies 

22:24 Rotenone exposure and microglial immune activation in Parkinson’s disease

29:24 Dopaminergic neuron vulnerability to pesticide exposure and mitochondrial dysfunction 

31:04 Familial Parkinson’s genes, polygenic Alzheimer’s risk, and genetically targeted clinical trials

33:13 Polygenic risk and microglial cell state regulation in Alzheimer’s disease

34:13 Defining cell states in single cell RNA sequencing

35:30 Oligodendrocyte epigenetic and transcriptional changes in Alzheimer’s disease

37:23 Sarah’s most memorable hiking adventures

38:58 Closing remarks

Find out more:

• Alzheimer’s APOE microglia xenotransplantation study

• Rotenone exposure Parkinson’s study