Association of CSF GAP-43 and APOE ε4 with Cognition in Mild Cognitive Impairment and Alzheimer’s Disease

Abstract

The growth-associated protein 43 (GAP-43) is a presynaptic phosphoprotein in cerebrospinal fluid (CSF). The ε4 allele of apolipoprotein E (APOE) is an important genetic risk factor for Alzheimer’s disease (AD). We aimed to evaluate the association of CSF GAP-43 with cognition and whether this correlation was related to the APOE ε4 status. We recruited participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, and they were divided into cognitively normal (CN) ε4 negative (CN ε4−), CN ε4 positive (CN ε4+), mild cognitive impairment (MCI) ε4 negative (MCI ε4−), MCI ε4 positive (MCI ε4+), AD ε4 negative (AD ε4−), and AD ε4 positive (AD ε4+) groups. Spearman’s 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 ε4+, AD ε4− and AD ε4+ groups compared with CN ε4− or MCI ε4− group. The negative associations between the CSF GAP-43 and MMSE scores at the baseline and follow-up were found in MCI ε4− and MCI ε4+ groups. In addition, baseline CSF GAP-43 was able to predict the clinical progression from MCI to AD. Conclusions: 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 ε4 status.

Systematic Analysis of Biological Processes Reveals Gene Co-expression Modules Driving Pathway Dysregulation in Alzheimer’s Disease

“…We noted GAP43, expressed in EXC-M3, whose elevated expression is recognized as a marker for tau and amyloid-driven pathologies. GAP43 also has a significant role in neural cell development, axonal sprouting, and regeneration (88–90). We also found enrichment of other AD-associated genes that have been prioritized as target genes in AD such as LINGO1 (EXC-M1) (91), NRGN (EXC-M1) (92), ADGRB3 (EXC-M2) (93), and RTN4 (EXC-M3) (94).…”

GAP-43 closely interacts with BDNF in hippocampal neurons and is associated with Alzheimer's disease progression

“…Targeting AD pathologies underlying the vulnerability of hippocampal neurons by amyloid-specific deprived molecules might be one of the possible therapeutic approaches to delay or halt AD progression. GAP-43 in cerebrospinal fluid (CSF) has previously been shown to be increased in AD and was correlated with the magnitude of Aβ plaques in the hippocampus, amygdala, and cortex, but was not associated with the α-synuclein or TDP-43 neuropathic molecules (Sandelius et al, 2019 ; Qiang et al, 2022 ; Zhu et al, 2022 ), supporting the notion that GAP-43 might be a marker for hippocampal neuronal cell degeneration, which are most vulnerable to AD pathogens. BDNF/TrkB neurotrophic activation is important in synaptic plasticity, neuronal survival, and hippocampal neuronal functions (Minichiello, 2009 ).…”

Biofluid biomarkers for Alzheimer’s disease

“…CSF GAP-43 increased with the cognitive decline, and it was correlated with Aβ plaque and NFT in hippocampus, amygdala, and cortex ( Sandelius et al, 2019 ). CSF GAP-43 could predict the progression from MCI to AD, and this correlation was suspected to be related with APOE ε4 ( Zhu et al, 2023 ). Elevated level of CSF GAP-43 was specific to AD compared to the other neurodegenerative diseases, e.g., MCI, ALS, behavioral variant FTD (bvFTD), PD, DLB, primary progressive aphasia (PPA), progressive supranuclear palsy, corticobasal syndrome, and posterior cortical atrophy (PCA).…”