{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T23:28:10Z","timestamp":1778542090112,"version":"3.51.4"},"reference-count":30,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:00:00Z","timestamp":1671580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key R&amp;D Program of Zhejiang","award":["2022C03161"],"award-info":[{"award-number":["2022C03161"]}]},{"name":"Key R&amp;D Program of Zhejiang","award":["81771498"],"award-info":[{"award-number":["81771498"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022C03161"],"award-info":[{"award-number":["2022C03161"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771498"],"award-info":[{"award-number":["81771498"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The growth-associated protein 43 (GAP-43) is a presynaptic phosphoprotein in cerebrospinal fluid (CSF). The \u03b54 allele of apolipoprotein E (APOE) is an important genetic risk factor for Alzheimer\u2019s disease (AD). We aimed to evaluate the association of CSF GAP-43 with cognition and whether this correlation was related to the APOE \u03b54 status. We recruited participants from the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) database, and they were divided into cognitively normal (CN) \u03b54 negative (CN \u03b54\u2212), CN \u03b54 positive (CN \u03b54+), mild cognitive impairment (MCI) \u03b54 negative (MCI \u03b54\u2212), MCI \u03b54 positive (MCI \u03b54+), AD \u03b54 negative (AD \u03b54\u2212), and AD \u03b54 positive (AD \u03b54+) groups. Spearman\u2019s correlation was utilized to evaluate the relationship between CSF GAP-43 and core AD biomarkers at the baseline. We performed receiver-operating characteristic (ROC) curve analyses to investigate the diagnostic accuracy of CSF GAP-43. The correlations between CSF GAP-43 and the Mini-Mental State Examination (MMSE) scores and brain atrophy at baseline were assessed by using multiple linear regression, while the association between CSF GAP-43 and MMSE scores at the follow-up was tested by performing the generalized estimating equation (GEE). The role of CSF GAP-43 in the conversion from MCI to AD was evaluated using the Cox proportional hazard model. We found that the CSF GAP-43 level was significantly increased in MCI \u03b54+, AD \u03b54\u2212 and AD \u03b54+ groups compared with CN \u03b54\u2212 or MCI \u03b54\u2212 group. The negative associations between the CSF GAP-43 and MMSE scores at the baseline and follow-up were found in MCI \u03b54\u2212 and MCI \u03b54+ groups. In addition, baseline CSF GAP-43 was able to predict the clinical progression from MCI to AD. CSF GAP-43 may be a promising biomarker to screen cognition for AD. The effects of CSF GAP-43 on cognition were suspected to be relevant to APOE \u03b54 status.<\/jats:p>","DOI":"10.3390\/cells12010013","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T03:59:26Z","timestamp":1671595166000},"page":"13","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Association of CSF GAP-43 and APOE \u03b54 with Cognition in Mild Cognitive Impairment and Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-151X","authenticated-orcid":false,"given":"Yueli","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8919-5750","authenticated-orcid":false,"given":"Xiaoming","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4161-1871","authenticated-orcid":false,"given":"Qin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China"},{"name":"Key Laboratory of Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6646-4954","authenticated-orcid":false,"given":"Yunmei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China"},{"name":"Key Laboratory of Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases of Zhejiang Province, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0140-6736(15)01124-1","article-title":"Alzheimer\u2019s disease","volume":"388","author":"Scheltens","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41583-019-0240-3","article-title":"Amyloid-\u03b2-independent regulators of tau pathology in Alzheimer disease","volume":"21","author":"Goldstein","year":"2020","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.neuropharm.2013.10.018","article-title":"Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment","volume":"79","author":"Counts","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/ana.410270502","article-title":"Synapse loss in frontal cortex biopsies in Alzheimer\u2019s disease: Correlation with cognitive severity","volume":"27","author":"DeKosky","year":"1990","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"293","DOI":"10.2174\/157015906778520782","article-title":"Molecular mechanisms, biological actions, and neuropharmacology of the growth-associated protein GAP-43","volume":"4","author":"Denny","year":"2006","journal-title":"Curr. Neuropharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3638","DOI":"10.1073\/pnas.85.10.3638","article-title":"Growth-associated protein GAP-43 is expressed selectively in associative regions of the adult human brain","volume":"85","author":"Neve","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","first-page":"934","article-title":"Aberrant GAP-43 gene expression in Alzheimer\u2019s disease","volume":"147","author":"Ng","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.neuroscience.2004.03.060","article-title":"Subfield-specific increase in brain growth protein in postmortem hippocampus of Alzheimer\u2019s patients","volume":"126","author":"Rekart","year":"2004","journal-title":"Neuroscience"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1002\/prca.201500150","article-title":"CSF profiling of the human brain enriched proteome reveals associations of neuromodulin and neurogranin to Alzheimer\u2019s disease","volume":"10","author":"Just","year":"2016","journal-title":"Proteom. Clin. Appl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.cca.2019.03.243","article-title":"Development of parallel reaction monitoring assays for cerebrospinal fluid proteins associated with Alzheimer\u2019s disease","volume":"494","author":"Andersson","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1126\/science.8346443","article-title":"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families","volume":"261","author":"Corder","year":"1993","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","article-title":"Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium","volume":"278","author":"Farrer","year":"1997","journal-title":"JAMA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/S1474-4422(20)30412-9","article-title":"APOE and Alzheimer\u2019s disease: Advances in genetics, pathophysiology, and therapeutic approaches","volume":"20","author":"Das","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1471-4159.2012.07908.x","article-title":"APOE genotype affects the pre-synaptic compartment of glutamatergic nerve terminals","volume":"124","author":"Dumanis","year":"2013","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.jalz.2010.03.006","article-title":"Clinical Core of the Alzheimer\u2019s Disease Neuroimaging Initiative: Progress and plans","volume":"6","author":"Aisen","year":"2010","journal-title":"Alzheimers Dement."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1212\/WNL.38.3.359","article-title":"The NINCDS-ADRDA Work Group criteria for the clinical diagnosis of probable Alzheimer\u2019s disease: A clinicopathologic study of 57 cases","volume":"38","author":"Tierney","year":"1988","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/ana.21610","article-title":"Cerebrospinal fluid biomarker signature in Alzheimer\u2019s disease neuroimaging initiative subjects","volume":"65","author":"Shaw","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jalz.2018.08.006","article-title":"Elevated CSF GAP-43 is Alzheimer\u2019s disease specific and associated with tau and amyloid pathology","volume":"15","author":"Sandelius","year":"2019","journal-title":"Alzheimers Dement."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1002\/jmri.21049","article-title":"The Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI): MRI methods","volume":"27","author":"Jack","year":"2008","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2307\/2531248","article-title":"Longitudinal data analysis for discrete and continuous outcomes","volume":"42","author":"Zeger","year":"1986","journal-title":"Biometrics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/1750-1326-9-53","article-title":"SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer\u2019s disease","volume":"9","author":"Brinkmalm","year":"2014","journal-title":"Mol. Neurodegener."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1016\/j.jalz.2014.10.009","article-title":"Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer\u2019s disease","volume":"11","author":"Kvartsberg","year":"2015","journal-title":"Alzheimers Dement."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/j.neuron.2010.11.030","article-title":"Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration","volume":"68","author":"Hoover","year":"2010","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1093\/brain\/awaa395","article-title":"Untangling the association of amyloid-\u03b2 and tau with synaptic and axonal loss in Alzheimer\u2019s disease","volume":"144","author":"Pereira","year":"2021","journal-title":"Brain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.neuron.2014.05.004","article-title":"The intersection of amyloid beta and tau at synapses in Alzheimer\u2019s disease","volume":"82","author":"Hyman","year":"2014","journal-title":"Neuron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11061","DOI":"10.1523\/JNEUROSCI.3034-05.2005","article-title":"Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses","volume":"25","author":"Roselli","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1111\/j.1460-9568.2006.04733.x","article-title":"Non-fibrillar beta-amyloid abates spike-timing-dependent synaptic potentiation at excitatory synapses in layer 2\/3 of the neocortex by targeting postsynaptic AMPA receptors","volume":"23","author":"Shemer","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/ana.410300410","article-title":"Physical basis of cognitive alterations in Alzheimer\u2019s disease: Synapse loss is the major correlate of cognitive impairment","volume":"30","author":"Terry","year":"1991","journal-title":"Ann. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1212\/01.wnl.0000260698.46517.8f","article-title":"Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment","volume":"68","author":"Scheff","year":"2007","journal-title":"Neurology"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/13\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:45:05Z","timestamp":1760147105000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/13"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,21]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12010013"],"URL":"https:\/\/doi.org\/10.3390\/cells12010013","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,21]]}}}