Biomarkers, Cognitive Function, and Mortality in Centenarians.

Abstract

Blood-based neural biomarkers linked to aging may provide insights into the biological end point of the human lifespan. However, the key biomarker associated with cognition and mortality in centenarians remains unclear. To investigate the associations between 3 neural biomarkers-amyloid-β42 and amyloid-β40 ratio (Aβ42/40), phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL)-and both cognitive function and all-cause mortality in centenarians. This population-based cohort study included Japanese centenarians aged 100 years or older who were enrolled between September 2000 and January 2021. Participants underwent baseline cognitive assessments and blood sampling and were followed up for 17 years for mortality. Data analysis was performed in February 2026. Baseline plasma levels of Aβ42/40, p-tau181, and NfL measured using ultrasensitive immunoassays. Cognitive function at baseline, measured using the Mini-Mental State Examination (MMSE), and all-cause mortality. Of 495 participants (398 [80.4%] women; mean [SD] age 104.1 [3.0] years), 419 completed a cognitive assessment (mean [SD] MMSE, 14.9 [6.9]). During 17 years of follow-up, 466 participants (95.5%) died. Lower Aβ42/40 (β = 0.99; 95% CI, 0.46 to 1.52) and higher NfL levels (β = -0.92; 95% CI, -1.62 to -0.23) were significantly associated with lower MMSE scores after adjusting for confounders. Higher NfL levels were also associated with increased mortality (hazard ratio, 1.36; 95% CI, 1.17 to 1.57), showing the greatest point estimate among the biomarkers, all of which were standardized and statistically significant (change in Akaike Information Criterion, likelihood ratio test, χ2 = 30.16; P < .001). Aβ42/40 and p-tau181 were not statistically significant after full adjustment. In this cohort study of centenarians, higher plasma NfL levels were associated with lower cognitive function and increased all-cause mortality, whereas Aβ42/40 and p-tau181 showed no associations. These findings suggest that plasma NfL was associated with neurodegeneration in extreme aging. Further studies are needed to confirm its clinical utility before routine implementation.