Objective:

Determine whether differences in microglial function exist in Alzheimer’s disease (AD) resilience.

Background:

AD is the most common neurodegenerative disease and a major challenge given the absence of any therapy that halts or reverses cognitive decline. AD resilience, defined as harboring the neuropathological hallmarks of AD (i.e., amyloid-β plaques and neurofibrillary tangles) but lacking the cognitive decline associated with dementia, represents an opportunity to identify novel mechanisms that may be leveraged to develop AD treatments. Microglia, the innate immune cells of the central nervous system, are linked to AD pathogenesis and may mediate aspects of AD resilience. 

Design/Methods:

Autopsy samples of dorsolateral prefrontal cortex were collected from a cohort of 35 human individuals with average age at death >80 years and post-mortem interval <8 hours. The cohort was comprised of 15 resilient individuals (cognitively unimpaired with AD neuropathology), 10 affected individuals (cognitively impaired with AD neuropathology), and 10 resistant controls (cognitively unimpaired without AD neuropathology) for the single-nucleus RNAseq, and 17 resilient, 10 affected, and 8 resistant individuals for the immunohistochemistry (IHC) dataset. Single-nucleus RNAseq of grey matter nuclei enriched for microglia using PU.1 FANS was used to measure gene expression profiles. IHC was done on separate sections to investigate microglial morphology with confocal microscopy.

Results:

Single-nucleus RNAseq demonstrated the expected diversity of microglial states, including multiple forms of homeostatic gene expressing microglia, as well as differences in the enrichment of certain microglial states in resilient versus affected individuals. Additionally, we found differences in gene expression between resilient and affected individuals within states. Confocal microscopy revealed a shift in microglial morphology between cohort groups.

Conclusions:

These results suggest that there are differences in microglial characteristics in AD resilience. Further characterization may identify targets that could be leveraged to develop new treatments that alter microglial states to mitigate AD-associated cognitive decline.