Proteomic signatures of protected APOE ε4 carriers reveal causal pathways associated with delayed Alzheimer's disease onset.

INTRODUCTION: APOE ε4 is the strongest common genetic risk factor for Alzheimer's disease (AD), yet many carriers remain cognitively unimpaired into late life. We tested whether protected ε4-first plasma proteomics could identify proteins associated with delayed clinical onset. METHODS: We analyzed harmonized Global Neurodegeneration Proteomics Consortium (GNPC) plasma proteomics. Protected ε4 carriers (ε3/ε4 ≥75 years; ε4/ε4 ≥65 years; Clinical Dementia Rating [CDR] score = 0; n = 456) were compared with ε4 carriers with AD (n = 1096). Protein-wise models adjusted for age, sex, ε4 dosage, and plasma proteomic principal components. Top signals were integrated with loss-of-function burden testing and plasma/cerebrospinal fluid Mendelian randomization. RESULTS: Protected ε4 status was associated with 721 protein measures. Integrated analyses prioritized LILRA5, DBI, BPNT1, PTEN, EPHA1, and PCDH10 as ε4-modified candidates and OMG, SELENOW, VAT1, and TPPP3 as broader AD-related signals. TREM2 and ACE were also identified. DISCUSSION: This strategy highlights immune, synaptic, metabolic-stress, and myelin/axonal pathways that may delay AD onset.