Presynaptic membrane protein dysfunction occurs prior to neurodegeneration and predicts faster cognitive decline

Abstract Introduction Although presynaptic loss measured by cerebrospinal fluid (CSF) growth‐associated protein‐43 (GAP‐43) is significantly involved in Alzheimer's disease (AD), the sequential association between CSF GAP‐43 and AD‐typical neurodegeneration is poorly understood. Methods We compared baseline CSF GAP‐43 levels ( n = 730) and longitudinal CSF GAP‐43 changes ( n = 327) in various biological stages of AD, and investigated their relationships with cross‐sectional and longitudinal measures of residual hippocampal volume, 18 F‐fluorodeoxyglucose PET, regional gray matter volume and cortical thickness, and cognition. Results Elevated CSF GAP43 levels were significantly associated with faster rates of hippocampal atrophy, AD‐signature hypometabolism and cortical thinning, and middle temporal gray matter atrophy‐related and AD‐signature hypometabolism‐related cognitive decline. In contrast, baseline levels of all these neurodegeneration biomarkers did not predict longitudinal CSF GAP‐43 increases. Discussion These findings suggest that presynaptic loss may occur prior to neurodegeneration, highlighting the importance of lowing tau aggregation and tau‐related synaptic dysfunction in elderly adults and AD patients.