Sarah Marzi
Dr. Sarah Marzi is a researcher specializing in epigenomics, transcriptomics, and neurodegenerative disorders. Her published research investigates molecular and epigenetic mechanisms in conditions such as Alzheimer's disease and Parkinson's disease, focusing on microglial pathways, chromatin states, and histone modifications. She also studies the application of artificial intelligence and machine learning to dementia genetics, methods optimization, and biomarker discovery.
27 claims checked on air: 1 context 1 overstated 25 supported
What they said on air - citing their own research
5 citing their own research
In Alzheimer's mouse models xenografted with human microglia, APOE4 microglia exhibit higher expression of pro-inflammatory cytokines, impaired protein phagocytosis, and downregulation of genes promoting cellular motility and proliferation compared to APOE2 microglia.
"the APOE4 microglia, as we've been talking about before, they are pro-inflammatory. They release a lot of pro-inflammatory cytokines. They're less good at clearing up proteins and other debris. So this ability to phagocytose is impaired. A third feature that we found was they seem to be less good at cellular motility and cellular proliferation. So normally when microglia are called into action to clear up something, they need to be motile, they need to proliferate, and they need to get to the site of injury or aggregation to clear up the proteins. And based on our gene expression results, we really see that genes that promote these kinds of processes are downregulated in the E4 microglia and actually conversely upregulated in the E2 microglia." (said at 0:26:13)
A 2025 study profiling gene expression and chromatin accessibility in human microglia xenografted into an Alzheimer's disease mouse model (APP NL-G-F) directly supports the claim. The researchers found that human APOE4 microglia showed downregulation of pathways and gene networks governing cellular proliferation and migration (motility) alongside altered immune responses, whereas APOE2 microglia exhibited enhanced phagocytic signatures and upregulation of these protective cellular functions.
In protective APOE2 microglia, there is enhanced signaling via binding of the vitamin D receptor to DNA.
"And one of the strongest results that we got for these enrichments is that in the E2, in the protective microglia, there seems to be enhanced signaling via binding to the DNA of the vitamin D receptor." (said at 0:30:19)
A 2025 study profiling the transcriptomic and chromatin accessibility landscapes of human microglia xenotransplanted into a mouse model of Alzheimer's disease demonstrated that APOE2 microglia exhibited enriched DNA-binding of the vitamin D receptor alongside increased phagocytic capacity, supporting a potential mechanism for APOE2's neuroprotective role.
In a rotenone rat model, there is a striking upregulation of the complement cascade and C1q in the substantia nigra.
"And uniquely in the substantia nigra, we actually see quite a striking upregulation of immune-related pathways, probably coming from the microglia, including an upregulation of an immune response called—so we see an upregulation of the complement cascade and potentially the C1q." (said at 0:44:41)
A 2025 study evaluating regional epigenomic and transcriptomic changes in a rotenone rat model of Parkinson's disease found region-specific immune alterations, specifically demonstrating a strong, rotenone-induced immune response in the substantia nigra characterized by increased activity in the C1q complement pathway. Because these findings are derived from an animal model, the GRADE certainty is very low.
In a 2018 study, widespread histone acetylation changes were found in the entorhinal cortex of Alzheimer's disease brains.
"And so we did um a big study of this um now 7, 8 years ago, 2018... and we showed that there are really widespread changes in this histone modification in the brains of people with Alzheimer's, and specifically in the brain region that is first and most severely affected by the disease." (said at 0:55:24)
A 2018 histone acetylome-wide association study led by Marzi and colleagues (Nature Neuroscience) quantified genome-wide histone H3 lysine 27 acetylation (H3K27ac) in post-mortem entorhinal cortex samples from individuals with Alzheimer's disease and matched controls. The authors identified widespread alterations in histone acetylation associated with Alzheimer's disease neuropathology, finding 4,162 differentially acetylated peaks enriched near genes implicated in amyloid-beta and tau pathology.
Epigenetic profiling of Alzheimer's disease brains reveals widespread epigenetic changes in both microglia and oligodendrocytes.
"what we see is that actually in Alzheimer's disease two cell types have really widespread changes epigenetically, and one is the microglia as we would have expected based on the genetics and based on a lot of our other work. But what surprised us a little bit is actually that even more strikingly, oligodendrocytes show really vast changes in the epigenetics." (said at 0:56:40)
Epigenomic profiling of postmortem human brain tissue across Alzheimer's disease cohorts demonstrates that while genetic risk loci for Alzheimer's disease are heavily enriched within microglia-specific regulatory regions, widespread disease-associated epigenetic alterations (such as differential H3K27 acetylation) predominantly map to oligodendrocytes and microglia.
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