Cortical transcriptional profiles in APOE4 carriers with Alzheimer's disease: Patterns of protection and degeneration

Transcriptional profiling of postmortem Alzheimer's disease (AD) brain tissue has yielded important insights into disease. We recently described a novel approach to understand transcriptional changes in AD designed to identify both neurosusceptibility and intrinsic neuroprotective factors in young non-AD E4 carriers. Here we extend our work to APOE4 related AD itself. In temporal cortex (BA 21), a region known to be vulnerable to AD pathology, we identified over 1400 transcripts that differed between APOE4 controls and APOE4 carriers diagnosed with AD. Results from somatosensory cortex (BA 1/2/3), a region relatively preserved inADdiffered strikingly from temporal cortex in that differences were far fewer (37 vs. 1492).We also conducted another set of contrasts involving APOE3 AD cases and APOE4 AD cases to better understand what transcriptional differences were dependent on genotype, but independent of disease status and found 6 transcripts to differ. We also conducted detailed pathway analyses in BA 1/2/3 and found significant transcriptional upregulations in pro-survival gene networks (e.g., TNF and NFkB). In summary, our results indicate that many of the molecular changes identified in the brains of patients with AD reflect the non-specific consequences of neurodegeneration, rather than causative processes. Additionally, the molecular signatures specific to somatosensory cortex may make it uniquely resistant to AD pathology and thereby could provide important leads for treatment.