Distinct Transcriptomic Responses to A beta plaques, Neurofibrillary Tangles, and APOE in Alzheimer's Disease

INTRODUCTIONOmics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimers disease (AD) but the spatial relationships with plaques and tangles and APOE-linked differences remain unclear. METHODSWe performed laser capture microdissection of A{beta} plaques, the 50m halo around them, tangles with the 50m halo around them, and areas distant (>50m) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing. RESULTSA{beta} plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. A{beta} plaques had more differentially expressed genes than tangles. We identified a gradient A{beta} plaque>peri-plaque>tangle>distant for these changes. AD APOE{varepsilon}4 homozygotes had greater changes than APOE{varepsilon}3 across locations, especially within A{beta} plaques. DISCUSSIONTranscriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with A{beta} plaques, and are exacerbated by the APOE{varepsilon}4 allele.