Association between plasma p-tau181 levels and the evolution of cognitive and physical performance in a cohort of cognitively impaired older adults with frailty criteria: Longitudinal data from the CogFrail study.

INTRODUCTION: Evidence linking plasma phosphorylated tau (p-tau)181 to cognitive decline comes from studies conducted in younger, selected research populations, raising questions about the generalizability of these findings to older adults meeting frailty criteria. The association between plasma p-tau181 and physical parameters has been sparsely investigated. This study aims to assess the relationship between plasma p-tau181 levels and the trajectories of cognitive and physical performance in a population of pre-frail and frail older adults. METHODS: This is a 2-year analysis based on longitudinal data from the CogFrail study. Plasma p-tau181 was measured using the SIMOA method. High p-tau181 levels were defined by a cut-off corresponding to the highest tertile of its distribution. Longitudinal changes from baseline in functional/cognitive (Mini-Mental State Examination [MMSE], Clinical Dementia Rating Sum of Boxes [CDR-SoB], Activities of Daily Living [ADL]-Index) and physical outcomes (gait speed, handgrip strength, Short Physical Performance Battery, and chair rise time) according to plasma p-tau181 status (high vs. low/intermediate levels) were compared using linear mixed-effects models. RESULTS: Among the 227 patients with available plasma p-tau181 concentrations (mean age: 82.1 ± 5.1 years, 63.4% women), 77 (33.9%) were classified as having high plasma p-tau181 levels. Mean plasma p-tau181 values were 14.64 (± 3.83) and 29.96 (± 7.63) pg/mL in the low/intermediate and high level groups, respectively. Over 2 years, participants with high p-tau181 levels showed greater progression in CDR-SoB (β = +0.43; 95% confidence interval [CI]: +0.24 to +0.63, log transformed), greater decline in MMSE (β = -2.09; 95% CI: -3.17 to -1.02), ADL (β = -0.31; 95% CI: -0.54 to -0.08), and handgrip strength (β = -2.66; 95% CI: -4.10 to -1.23), compared to those with low/intermediate levels. DISCUSSION: In a population of pre-frail and frail older adults with cognitive impairment, individuals with elevated plasma p-tau181 levels showed greater cognitive and physical deterioration over a 2-year period. Age-related loss of proteostasis, responsible for amyloidopathy and associated tauopathy, may play a role not only in cognitive but also in physical decline, representing a potential target for preventive and therapeutic interventions.