Associations Between Blood-Based Biomarkers and Cognitive and Functional Trajectories Among Participants of the MEMENTO Cohort

Abstract

Background and Objectives Elevated levels of Alzheimer disease (AD) blood-based biomarkers are associated with accelerated cognitive decline. However, their distinct relationships with specific cognitive and functional domains require further investigation. We aimed at estimating the associations between AD blood-based biomarkers and the trajectories of distinct cognitive and functional domains over a 5-year follow-up period. Methods We conducted a clinic-based prospective study using data from the MEMENTO study, a nationwide French cohort. We selected dementia-free individuals at baseline aged 60 years or older. Baseline measurements of β-amyloid (Aβ) 40 and 42, phosphorylated tau (p-tau181), and neurofilament light chain (NfL) concentrations were obtained using the Simoa HD-X analyzer. Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT), animal fluency, Trail Making Tests A and B, Short Physical Performance Battery (SPPB), and Instrumental Activities of Daily Living were administered annually for up to 5 years. We used linear mixed models, adjusted for potential confounders, to model AD biomarkers’ relation with cognitive and functional decline. Results A total of 1,938 participants were included in this study, with a mean (SD) baseline age of 72.8 (6.6) years, and 62% were women. Higher baseline p-tau181 and NfL were associated with significantly faster decline in most cognitive, physical, and functional outcomes (+1 SD p-tau181: β MMSE = −0.055, 95% CI −0.067 to −0.043, β FCSRT = −0.034, 95% CI −0.043 to −0.025, β fluency = −0.029, 95% CI −0.038 to −0.020, β SPPB = −0.040, 95% CI −0.057 to −0.022, and β 4IADL = −0.115, 95% CI 0.091–0.140. +1 SD NfL: β MMSE = −0.039, 95% CI −0.053 to −0.025, β FCSRT = −0.022, 95% CI −0.032 to −0.012, β fluency = −0.014, 95% CI −0.024 to −0.004, and β 4IADL = 0.077, 95% CI 0.048–0.105). A multiplicative association of p-tau181 and NfL with worsening cognitive and functional trajectories was evidenced. Lower Aβ42/40 ratio was only associated with slightly faster cognitive decline in FCSRT and semantic fluency (+1 SD: β = 0.011, 95% CI 0.002–0.020, and β = 0.011, 95% CI 0.003–0.020, respectively). These associations were not modified by APOE ε4, sex, nor education level. Discussion In a memory clinic sample, p-tau181 and NfL, both independently and jointly, are linked to more pronounced cognitive, physical and functional declines. Blood-based biomarker measurement in AD research may provide useful insights regarding biological processes underlying cognitive, physical, and functional declines in at-risk individuals.