Presynaptic loss and axonal degeneration synergistically correlate with longitudinal neurodegeneration and cognitive decline.

INTRODUCTION

Baseline and longitudinal characteristics of cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) and plasma neurofilament light (NfL) and how they correlate interactively with neurodegeneration and cognitive decline in Alzheimer's disease (AD) are not fully understood.

METHODS

We investigated dynamic changes of CSF GAP-43 and plasma NfL across different AD stages and their association with longitudinal neurodegeneration and cognitive decline up to 12 years.

RESULTS

Individuals with hippocampal atrophy, AD-signature cortical thinning, or hypometabolism (N+) had faster plasma NfL increase rates than healthy individuals, regardless of amyloid/tau status. In contrast, none of these N+ imaging indicators correlated with more rapid increases in CSF GAP-43. Furthermore, CSF GAP-43 and plasma NfL synergistically predicted subsequent gray matter atrophy, cortical thinning, hypometabolism of the middle temporal region, and cognition.

DISCUSSION

CSF GAP-43-associated presynaptic loss indicates tau-dependent early neurodegeneration, whereas the axonal degeneration indicated by plasma NfL is a relatively late atrophy/hypometabolism-associated fluid neurodegeneration biomarker.

HIGHLIGHTS

Plasma neurofilament light (NfL) was increased in N+ or cognitively impaired individuals. Increases in tau-dependent cerebrospinal fluid CSF growth-associated protein 43 (GAP-43) before imaging neurodegeneration indicators. CSF GAP-43 and plasma NfL are synergistically related to longitudinal neurodegeneration. CSF GAP-43 and plasma NfL are synergistically related to longitudinal cognitive decline.