Cross-tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer’s disease

APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), but its contribution to disease pathogenesis remains incompletely understood. Here, we integrate proteomic profiling of plasma, cerebrospinal fluid (CSF), and brain tissue from over 10,000 individuals to define the immune phenotype associated with APOE ε4. We identify a conserved, allele dose-dependent pro-inflammatory immune signature across peripheral and central tissues independent of AD diagnosis. This signature is enriched in adaptive immune cells and white matter-resident glial and vascular cells. It also emerges in patient-derived cortical organoids prior to amyloid-β and tau pathology, supporting a causal, 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. 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.