Proteomic Signatures of Protected APOE-ϵ4 Carriers Reveal Causal Pathways Associated with Delayed Alzheimer's Disease Onset

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSAPOE-{varepsilon}4 is the strongest common genetic risk factor for Alzheimers disease (AD), yet many carriers remain cognitively unimpaired into late life. We tested whether a protected-{varepsilon}4-first proteomic approach could identify plasma proteins associated with delayed clinical onset among {varepsilon}4 carriers. METHODSWe analyzed harmonized plasma proteomics from the Global Neurodegeneration Proteomics Consortium. Protected {varepsilon}4 carriers ({varepsilon}3/{varepsilon}4 aged [≥]75 years; {varepsilon}4/{varepsilon}4 aged [≥]65 years; CDR=0; n=456) were compared with {varepsilon}4 carriers with AD (n=1,096). Protein-wise linear models adjusted for age, sex, {varepsilon}4 dosage, and plasma proteomic principal components. Top signals were integrated with high-confidence loss-of-function burden testing and plasma/CSF Mendelian randomization. RESULTS{varepsilon}4 protected was associated with 721 protein levels. Integrated analyses prioritized proteins linked to {varepsilon}4-modified disease biology, including LILRA5, DBI, BPNT1, PTEN, EPHA1, and PCDH10, and proteins aligned with broader AD-related change, including OMG, SELENOW, VAT1, and TPPP3. TREM2 and ACE were also identified, providing internal biological validation of the approach. DISCUSSIONA protected-{varepsilon}4-first plasma proteomic strategy highlights immune, synaptic, metabolic-stress, and myelin/axonal pathways that may delay AD onset and helps prioritize candidate {varepsilon}4-specific modifiers for prevention-focused therapeutics.