Donor specific transcriptomic analysis of Alzheimer’s disease associated hypometabolism highlights a unique donor, ribosomal proteins and microglia
Alzheimer’s disease (AD) starts decades before clinical symptoms appear. Low glucose utilization in regions of the cerebral cortex marks early AD. To identify these regions, we conducted a voxel-wise meta-analysis of previous studies carried out with positron emission tomography that compared AD patients with healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes that show spatial correlation across the cerebral cortex between their expression and this hypometabolism. Of the six brains in the Atlas, one demonstrated a strong spatial correlation between gene expression and hypometabolism. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when comparing this donor’s brain with the other five donors. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which encode primarily cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes increases progressively across AD-associated states of microglial activation. In addition, genes involved in cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, and vacuole sorting are associated with the hypometabolism map. These genes suggest disruption of the protein life cycle and neuroimmune activation. Taken together, our molecular characterization reveals a link to AD-associated hypometabolism that may be relevant to preclinical stages of AD.
Significance Statement Fluorodeoxyglucose positron emission tomography (FDG-PET) is a frontline tool for the diagnosis of dementia. We sought to determine the molecular underpinnings of the metabolic signatures of Alzheimer’s disease revealed by FDG-PET. We found that of the six brains in the Allen Human Brain Atlas, a set of ribosomal proteins strongly aligned with the hypometabolism map in one of the six Atlased brains. While this brain was from a 39-year-old, it contained a neurofibrillary tangle in the entorhinal cortex. We observe changes in estimated neuron and microglia proportions that also suggest this individual had prodromal Alzheimer’s disease. In other studies, expression of the ribosomal genes increases across Alzheimer’s disease-associated microglial activation.