Abstract
INTRODUCTION: Whether Alzheimer's disease (AD)-associated plasma biomarkers reflect cognitive performance and neuropathology in the oldest old remains unclear. METHODS: In plasma samples from 255 centenarians from the longitudinal 100-plus Study (median age 101.2 years), we quantified biomarkers amyloid beta (Aβ)42/40 ratio, Aβ40, Aβ42, phosphorylated tau 181 (pTau-181)/Aβ42 ratio, pTau-181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) concentrations. These were associated with same-day measures of cognitive performance and, for centenarians who donated their brain (n = 60), with post mortem Aβ and tau neuropathology. RESULTS: Cognition ranged from high to early cognitive decline (median Mini-Mental State Examination [MMSE] score = 26). Lower plasma Aβ40 and Aβ42 are associated with poorer executive functioning, attention/processing speed, and higher Aβ neuropathology. Elevated plasma NfL and GFAP are associated with poorer executive functioning, slower processing speed, and Aβ and tau neuropathology. Higher plasma pTau-181 and the pTau-181/Aβ42 ratio are associated with Aβ and tau neuropathology, but not with cognitive performance. The Aβ42/40 ratio was uninformative. DISCUSSION: Plasma Aβ, NfL, and GFAP detected neuropathology and early cognitive decline in centenarians; plasma pTau-181 and the pTau-181/Aβ42 ratio primarily report more advanced neuropathology. HIGHLIGHTS: Lower plasma Aβ40 and Aβ42 concentrations are associated with poorer executive functioning and higher Aβ neuropathology, and thus may detect early cognitive decline in centenarians. Higher plasma pTau-181 concentrations and the pTau-181/Aβ42 ratio are strongly associated with Aβ and tau neuropathology; however, they are not associated with cognitive performance. Higher NfL concentrations are associated with higher Aβ and tau neuropathology. Higher plasma NfL and GFAP concentrations are associated with poorer attention and processing speed and may detect early cognitive decline in centenarians.