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CSF PROTEOME CHANGES DEPEND ON APOE GENOTYPE, AGE AND SEX IN PRODROMAL AD
Abstract
Aims
APOE, a major genetic risk factor for Alzheimer’s disease (AD), shows a complex interaction with age and sex on CSF amyloid and tau biomarkers in prodromal AD. We studied whether sex-, age-, and APOE-dependent alterations in the CSF proteome can be defined by distinct biological processes.
Methods
CSF proteomics analysis was performed using TMT-MS in 77 prodromal AD individuals from EMIF (age 70 years, 42 (55%) female). 1178 proteins were detected in ≥54 (70%) individuals. Associations between protein concentrations and APOE genotype were tested with linear regressions including a three-way interaction between APOE, age and sex. The STRING database was used for biological pathway enrichment analysis on proteins with significant interaction-terms (p-values<0.1).
Results
Two hundred and thirty-five (20%) proteins had a significant interaction between APOE, age and sex. Females showed linear APOE Ɛ4 dosage effects on protein concentrations depending on age: younger Ɛ4Ɛ4 females (<70 years) had high levels of proteins involved in neuronal plasticity pathways, while these proteins were low in older Ɛ4Ɛ4 females. Males showed non-linear APOE Ɛ4 dosage effects depending on age: younger Ɛ3Ɛ4 males had high levels of neuronal plasticity-related proteins, and low levels of proteins involved in the complement and coagulation cascade, while in older Ɛ3Ɛ4 males these proteins showed changes in the opposite direction.
Conclusions
The CSF proteome of prodromal AD individuals shows sex-, age- and APOE Ɛ4 dose-dependent alterations, which were associated with distinct biological processes, including neuronal plasticity and in males also complement and coagulation pathways. These differences should be considered in future therapy development.