The Trajectory of Cerebrospinal Fluid Growth-Associated Protein 43 in the Alzheimer’s Disease Continuum: A Longitudinal Study

Article type: Research Article

Authors: Zhang, Heng^{a; 1} | Lyu, Diyang^{a; 1} | Jia, Jianping^{a; b; c; d; e; *} | for the Alzheimer’s Disease Neuroimaging Initiative²

Affiliations: [a] Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China | [b] Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, China | [c] Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing, China | [d] Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China | [e] Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, China

Correspondence: [*] Correspondence to: Prof Jianping Jia, Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China. E-mail: jjp@ccmu.edu.cn.

Note: [1] These authors contributed equally to this work.

Note: [2] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer’s disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. Objective:To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. Methods:CSF GAP-43 was analyzed in 788 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. Results:CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. Conclusion:CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials.

Keywords: Alzheimer’s disease, biomarker, growth-associated protein 43, synaptic dysfunction

DOI: 10.3233/JAD-215456

Journal: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1441-1452, 2022