Donor specific transcriptomic analysis of Alzheimer's disease associated hypometabolism highlights a unique donor, microglia, and ribosomal proteins

Abstract

Alzheimers disease (AD) starts decades before clinical symptoms appear. Low glucose utilization in regions of the cerebral cortex marks early AD and is clinically useful. To identify these regions, we conducted a voxel-wise meta-analysis of positron emission tomography studies that compared AD patients with healthy controls. This meta-analysis included 27 studies that assayed glucose utilization in 915 AD patients and 715 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 with expression patterns associated with this hypometabolism pattern in the cerebral cortex. Of the six brains in the Atlas, one demonstrated a strong spatial association with the hypometabolism pattern. 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 compared with the other five brains. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which primarily encode cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes progressively increases 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 of cortical hypometabolism reveals a molecular link to AD associated hypometabolism that may be relevant to preclinical stages.