Specific associations between plasma biomarkers and postmortem amyloid plaque and tau tangle loads

Abstract

Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates have not yet been fully determined. To investigate and compare independent associations between multiple plasma biomarkers (p‐tau181, p‐tau217, p‐tau231, Aβ42/40, GFAP, and NfL) and neuropathologic measures of amyloid and tau, we included 105 participants from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with antemortem plasma samples and a postmortem neuropathological exam, 48 of whom had longitudinal p‐tau217 and p‐tau181. When simultaneously including plaque and tangle loads, the Aβ42/40 ratio and p‐tau231 were only associated with plaques (ρ Aβ42/40 [95%CI] = −0.53[−0.65, −0.35], ρ p‐tau231 [95%CI] = 0.28[0.10, 0.43]), GFAP was only associated with tangles (ρ GFAP [95%CI] = 0.39[0.17, 0.57]), and p‐tau217 and p‐tau181 were associated with both plaques (ρ p‐tau217 [95%CI] = 0.40[0.21, 0.56], ρ p‐tau181 [95%CI] = 0.36[0.15, 0.50]) and tangles (ρ p‐tau217 [95%CI] = 0.52[0.34, 0.66]; ρ p‐tau181 [95%CI] = 0.36[0.17, 0.52]). A model combining p‐tau217 and the Aβ42/40 ratio showed the highest accuracy for predicting the presence of Alzheimer's disease neuropathological change (ADNC, AUC[95%CI] = 0.89[0.82, 0.96]) and plaque load ( R 2  = 0.55), while p‐tau217 alone was optimal for predicting tangle load ( R 2  = 0.45). Our results suggest that high‐performing assays of plasma p‐tau217 and Aβ42/40 might be an optimal combination to assess Alzheimer's‐related pathology in vivo . image This study conducted a head‐to‐head comparison between multiple plasma biomarkers and neuropathological measures of amyloid plaques and neurofibrillary tangles. Plasma p‐tau217 and p‐tau181 are independently associated with both amyloid plaques and tau neurofibrillary tangles, the main pathological hallmarks of Alzheimer's disease. Plasma p‐tau217 may be a better Alzheimer's biomarker than p‐tau181 as it shows stronger associations with Alzheimer's pathology and is more sensitive to early pathological changes. Plasma p‐tau217 longitudinal changes may help in predicting the presence of Alzheimer's pathology. Plasma Aβ42/40 and plasma p‐tau231 are specifically associated with amyloid pathology, whereas plasma glial fibrillary acidic protein (GFAP) is specifically associated with tau pathology. Plasma neurofilament light (NfL) is increased in participants with cerebral white matter rarefaction even after accounting for the presence of Alzheimer's disease pathology.