Elevated CSF GAP43 is driven by tau aggregation rather than β‐amyloid and neurodegeneration in Alzheimer’s disease

Abstract

AbstractBackgroundCerebrospinal fluid (CSF) pre‐synaptic protein growth‐associated protein 43 (GAP43) appears to be closely linked to neurodegeneration and cognitive decline in Alzheimer’s disease (AD). However, it is not well characterized about the associations of CSF GAP43 with β‐amyloid (Aβ), tau, neurodegeneration and cognitive decline.MethodWe identified 790 Alzheimer’s Disease Neuroimaging Initiative participants with concurrent CSF GAP43, Aβ PET, CSF p‐Tau181, residual hippocampal volume (rHCV), 18F‐fluorodeoxyglucose (FDG) PET and cognitive assessments within one year. Among of them, 340 individuals had longitudinal CSF GAP43 measurements. We compared baseline and longitudinal changes of CSF GAP43 among different biological stages defined by Aβ PET (A), CSF p‐Tau181 (T) and rHCV (N) in addition to their associations with Aβ PET, CSF p‐Tau181, rHCV, FDG PET and cognition cross‐sectionally and longitudinally, controlling for age, sex, APOE‐ε4 status and diagnosis.ResultAmong different A/T and A/T/N profiles, we found all CSF p‐Tau181‐positive individuals had significant higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases regardless of Aβ deposition and hippocampal atrophy (Figure 1). Furthermore, increased CSF p‐Tau181 rather than Aβ PET was related to higher baseline CSF GAP43 and faster rates of CSF GAP43 increases regardless of A/T profiles (Figure 2). In the subgroups of individuals with longitudinal MRI, FDG PET and cognition data, we found that higher CSF GAP43 concentrations (n = 377) and faster rates of GAP43 increases (n = 240) were associated with faster hippocampal atrophy, hypometabolism and cognitive decline (Figure 3).ConclusionThese findings imply that tau aggregation rather than Aβ pathology is driving pre‐synaptic loss measured by CSF GAP43, which subsequently contributes to hippocampal atrophy and hypometabolism, resulting in cognitive decline in AD. Altogether, CSF GAP43 may be considered for an extra biomarker beyond A/T/N biomarkers, which can provide new insights into underlying AD pathogenesis prior to neurodegeneration.