Artur Shvetcov, Shannon Thomson, Mark E Graham, Brittany Hauger, Jessica E Keller, Christine J Smoyer, Sarah E Tague, Ann-Na Cho, Farhad B Imam, Varsha Krish, Global Neurodegeneration Proteomics Consortium (GNPC), Matthew K Taylor, Jonathan D Mahnken, Debra K Sullivan, Joanne H Reed, Jeffrey M Burns, Chad Slawson, Russell H Swerdlow, Heather M Wilkins, Caitlin A Finney
We identify a conserved, allele dose-dependent pro-inflammatory immune protein signature across peripheral and central tissues independent of AD diagnosis. This signature also emerges in patient-derived cortical organoids prior to amyloid beta and tau pathology, supporting a genotype-driven mechanism. Cross-tissue comparisons reveal shared innate and antiviral responses alongside tissue-specific immune signaling. Notably, a 12-week medical ketogenic diet partially reversed the APOE ε4 immune signature.
INTRODUCTION: Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood.
METHODS: Here, we integrate proteomic profiling of plasma (n = 9028), cerebrospinal fluid (n = 1099), dorsolateral prefrontal cortex (n = 720), and superior temporal gyrus (n = 105) to define the immune phenotype associated with APOE ε4.
RESULTS: We identify a conserved, allele dose-dependent pro-inflammatory immune protein signature across peripheral and central tissues independent of AD diagnosis. This signature also emerges in patient-derived cortical organoids prior to amyloid beta and tau pathology, supporting a genotype-driven mechanism. Cross-tissue comparisons reveal shared innate and antiviral responses alongside tissue-specific immune signaling. Notably, a 12-week medical ketogenic diet partially reversed the APOE ε4 immune signature.
DISCUSSION: These findings position immune dysregulation as an early and tractable driver of AD risk in APOE ε4 carriers with direct implications for targeted prevention strategies.