Proteomic signatures of protected APOE ε4 carriers reveal causal pathways associated with delayed Alzheimer's disease onset
Yann Le Guen, Junyoung Park, Andrés Peña‐Tauber, Michael D. GreiciusAbstract
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.