Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Cross-tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease.
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Shvetcov Artur, Thomson Shannon, Graham Mark E, Hauger Brittany, Keller Jessica E, Smoyer Christine J, Tague Sarah E, Cho Ann-Na, Imam Farhad B, Krish Varsha, Global Neurodegeneration Proteomics Consortium (GNPC), Taylor Matthew K, Mahnken Jonathan D, Sullivan Debra K, Reed Joanne H, Burns Jeffrey M, Slawson Chad, Swerdlow Russell H, Wilkins Heather M, Finney Caitlin A
Аннотация
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.
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.