Frontal cortex pyramidal neuron expression profiles differentiate the prodromal stage from progressive degeneration across the Alzheimer’s disease spectrum

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder affecting an estimated 6.9 million Americans. There is no current treatment to prevent the onset or progression of dementia. Therefore, it is imperative to identify molecular and cellular mechanism(s) underlying the pathobiology of AD onset and progression. We employed laser capture microdissection (LCM) to isolate layer III pyramidal neurons from postmortem human prefrontal cortex Brodmann area 9 (BA9) tissue. Single population RNA-sequencing was conducted utilizing tissue from subjects across the AD spectrum, including individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. Differentially expressed genes (DEGs) were compared and contrasted across groups. The number of DEGs increased from Prodromal (MCI versus NCI; 1,306 DEGs) to Progression (AD versus MCI; 2,505 DEGs) to Frank AD (AD versus NCI; 3,259 DEGs). Bioinformatic inquiry revealed alterations in key pathways during disease progression including oxidative phosphorylation, mitochondrial dysfunction, and immune responses suggesting dysfunctional bioenergetics in vulnerable corticocortical projection neurons. The majority of DEGs and pathways shared between Prodromal and Progression exhibited a change in the direction of dysregulation, termed ‘directionally divergent’. In contrast, the majority of common DEGs and pathways between the later stage Progression and Frank AD remained in the same direction, termed ‘directionally convergent’. Candidate genes and pathways were identified that demarcate early-stage AD onset (Prodromal) differentially from AD progression (Progression and Frank AD) providing a roadmap to study cortical cellular vulnerability and key targets for intervention at early stages of AD.