Distinct Transcriptomic Responses to Aβ plaques, Neurofibrillary Tangles, and APOE in Alzheimer’s Disease

INTRODUCTION: Omics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer’s disease (AD) but the spatial relationships with plaques and tangles and APOE-linked differences remain unclear. METHODS: We performed laser capture microdissection of Aβ plaques, the 50μm halo around them, tangles with the 50μm halo around them, and areas distant (>50μm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA-sequencing. RESULTS: Aβ plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Aβ plaques had more differentially expressed genes than tangles. We identified a gradient Aβ plaque>peri-plaque>tangle>distant for these changes. AD APOEε4 homozygotes had greater changes than APOEε3 across locations, especially within Aβ plaques. DISCUSSION: Transcriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Aβ plaques, and are exacerbated by the APOEε4 allele.