Proteome-wide association study of cortical proteins that may provide resilience for late-life disability

Disabilities are common and untreatable in many older adults. This proteome-wide discovery study identified cortical proteins that may provide resilience for disabilities in older adults. Participants were 850 decedents (mean age 89.3 years [SD: 6.6] at death, 67% female) from two longitudinal cohort studies with proteome-wide data collected from the dorsal lateral prefrontal cortex, indices of 10 Alzheimer's disease and related dementia (ADRD) pathologies, and measures of mobility disability, instrumental activities of daily living (IADLs), and activities of daily living (ADLs) prior to death. Linear regression models adjusting for demographics identified proteins related to each disability phenotype correcting for multiple comparisons (p < 5 × 10-6). Resilience proteins-operationalized as proteins related to residual disability after adjusting for ADRD pathologies-were aggregated into resilience index scores for each disability instrument and their associations with adverse health outcomes were tested. Exploratory functional enrichment analyses identified molecular pathways associated with resilience proteins. We identified 12 resilience proteins related to mobility disability, 215 for IADL and 291 for ADL disability. Models with resilience index scores accounted for an additional 2.7%, 3.3%, and 3.5% of the variance of mobility, IADL, and ADL disability, respectively, compared to 1.7%, 2.7% and 2.0%, for ADRD pathologies. In exploratory analyses, key enriched Gene Ontology terms were predominantly related to mitochondrial function. Further work targeting these cortical proteins is needed to demonstrate that they provide resilience for disability in older adults and can facilitate functional independence in old age, though future work is needed to demonstrate protective mechanisms. Ultimately, targeting these proteins may lead to therapies that maintain functional independence in aging adults.