Association of Presynaptic Loss with Alzheimer's Disease and Cognitive Decline.

Objective: Increased presynaptic dysfunction measured by cerebrospinal fluid (CSF) growth-associated protein-43 (GAP43) may be observed in Alzheimer's disease (AD), but how CSF GAP43 increases relate to AD-core pathologies, neurodegeneration, and cognitive decline in AD requires further investigation.

Methods: We analyzed 731 older adults with baseline β-amyloid (Aβ) positron emission tomography (PET), CSF GAP43, CSF phosphorylated tau181 (p-Tau ), and F-fluorodeoxyglucose PET, and longitudinal residual hippocampal volume and cognitive assessments. Among them, 377 individuals had longitudinal F-fluorodeoxyglucose PET, and 326 individuals had simultaneous longitudinal CSF GAP43, Aβ PET, and CSF p-Tau data. We compared baseline and slopes of CSF GAP43 among different stages of AD, as well as their associations with Aβ PET, CSF p-Tau , residual hippocampal volume, F-fluorodeoxyglucose PET, and cognition cross-sectionally and longitudinally.

Results: Regardless of Aβ positivity and clinical diagnosis, CSF p-Tau -positive individuals showed higher CSF GAP43 concentrations (p < 0.001) and faster rates of CSF GAP43 increases (p < 0.001) compared with the CSF p-Tau -negative individuals. Moreover, higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases were strongly related to CSF p-Tau independent of Aβ PET. They were related to more rapid hippocampal atrophy, hypometabolism, and cognitive decline (p < 0.001), and predicted the progression from MCI to dementia (area under the curve for baseline 0.704; area under the curve for slope 0.717) over a median 4 years of follow up.

Interpretation: Tau aggregations rather than Aβ plaques primarily drive presynaptic dysfunction measured by CSF GAP43, which may lead to sequential neurodegeneration and cognitive impairment in AD or neurodegenerative diseases. ANN NEUROL 2022;92:1001-1015.