Baseline Physical Frailty Predicts Clinical Outcomes During Lecanemab Therapy in Early Alzheimer's Disease: A Prospective Real-World Cohort Study.

BACKGROUND: Physical frailty and sarcopenia are recognized as determinants of Alzheimer's disease (AD) progression, but their implications during anti-amyloid therapy remain unclear. We investigated their associations with longitudinal cognitive outcomes, treatment safety, tolerability, and plasma p-tau217 trajectories in patients with early AD receiving lecanemab. METHODS: This prospective cohort included 187 patients with amyloid-positive early AD who initiated lecanemab at a tertiary memory clinic. Physical frailty was defined using the Short Physical Performance Battery (SPPB), and sarcopenia according to the 2019 Asian Working Group for Sarcopenia criteria. Logistic regression was used for infusion-related reactions (IRRs) and treatment discontinuation, whereas amyloid-related imaging abnormalities (ARIA) outcomes were evaluated using Firth penalized logistic regression because of the limited number of events. Longitudinal cognitive outcomes and plasma p-tau217 trajectories were analyzed using linear mixed-effects models. RESULTS: SPPB-defined physical frailty and sarcopenia were associated with faster CDR-SB worsening (β = 1.52 and 1.40 points/year, respectively; both nominal p<0.001; both q<0.001). A greater decline in SNSB-D was observed in participants with SPPB-defined physical frailty (β=-11.36 points/year; 95% CI, -22.38 to -0.34; nominal p=0.044), although this association did not remain statistically significant after FDR correction (q=0.065). Neither exposure was associated with MMSE change. SPPB-defined physical frailty was associated with a higher risk of IRRs (adjusted odds ratio, 4.75; 95% confidence interval, 2.03-11.66; p<0.001), but was not associated with ARIA or treatment discontinuation. No differential plasma p-tau217 trajectories were detected according to baseline SPPB-defined physical frailty or sarcopenia status. CONCLUSIONS: Baseline SPPB-defined physical frailty was associated with longitudinal clinical progression and IRRs during lecanemab treatment. These findings suggest that SPPB-defined physical frailty may represent a candidate prognostic marker of clinical outcomes during lecanemab therapy and warrant further validation in larger cohorts.