Identifying motor resilience proteins associated with motor decline in older adults.

BACKGROUND

This study will identify cortical proteins that may provide motor resilience, the capacity to maintain motor function despite underlying Alzheimer's disease and related dementias (ADRD) pathologies.

METHODS

We studied 850 decedents with postmortem indices of 10 ADRD pathologies and proteome from dorsal lateral prefrontal cortex. Annual parkinsonian signs were assessed using a modified Unified Parkinson Disease Rating Scale. First, we adjusted linear models for ADRD pathologies to isolate resilience proteins, unrelated to ADRD pathologies, but that were related to linear motor decline. Next, functional mixed effects (FMEs) models were used to determine if resilience proteins were related to non-linear motor decline. Exploratory functional enrichment was then used to assess pathways underlying motor resilience proteins.

RESULTS

Mean age at death was 90 years (SD = 6.4), 69% female and 7 years follow-up. Adjusting linear models for age, sex, and ADRD pathologies, we isolated thirteen proteins that may provide motor resilience (Bonferroni correction p < 5 × 10-6). FME models showed, that on average, progression of parkinsonian signs was non-linear from 25 to 12 years before death, followed by accelerated linear decline until death. Five of thirteen resilience proteins were also related to non-linear decline. Motor resilience may be supported by a coordinated network of proteins that help to preserve neuronal structure, cellular transport, and synaptic integrity, functions critical for diverse aging phenotypes.

CONCLUSIONS

Cortical proteins may provide motor resilience for both linear and non-linear motor decline. Further drug discovery targeting resilience proteins may yield therapies that can reduce motor impairment even in the absence of treatments for ADRD pathologies.