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 amyloid beta (Aβ) plaques, the 50 μm halo around them, tangles with the 50 μm halo around them, and areas distant (> 50 μm) 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 APOE ε4 homozygotes had greater changes than APOE ε3 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 APOE ε4 allele.