Plasma proteomic signatures of dual cognitive and mobility decline in older adults.

Background: The simultaneous memory and gait decline is linked to greater dementia risk than memory decline alone. We aim to identify dual decline-related protein changes that may offer valuable insights into biological processes.

Methods: We compared longitudinal changes in 7268 plasma proteomic markers in older adults experiencing dual decline, memory decline, and gait decline from no decline (reference) using linear mixed-effects regression and related to brain MRI and blood biomarkers.

Findings: There were no baseline group differences in proteins. Longitudinally, only dual decline showed significant changes in 75 proteins, with PGP9.5 showing the most alteration (p-FDR < 0.05), implicated in synaptic function, proteostasis, and regulation of amyloid precursor protein and amyloid β protein. The top-enriched pathway pointed to mitochondrial protein degradation. Of 75, changes in select proteins were related to future cognitive impairment, brain atrophy patterns, and blood biomarkers of AD, neuroinflammation, and neurodegeneration, with TRI72 being the top significant protein related to cognitive impairment and pTau181 progression.

Interpretation: Older adults experiencing dual decline exhibit longitudinal protein changes, indicating mitochondrial dysfunction, proteostasis, neuroinflammation, and immune responses.

Funding: None.